Device For Promotion Of Hemostasis And/or Wound Healing

ABSTRACT

The present invention relates to a matrix material comprising a pharmaceutical composition such as a matrix material with a pharmaceutical composition printed on the surface. In one embodiment the pharmaceutical composition comprises thrombin. The invention further describes a method for making the matrix material with a pharmaceutical composition printed on the surface. In one specific embodiment the invention also relates to the use of said matrix material for promotion of hemostasis and/or wound healing. The invention also relates to a kit-of-parts comprising a matrix with a pharmaceutical composition and a container with a peelable lid.

This application is a continuation of U.S. application Ser. No.12/919,643, filed Feb. 27, 2009, which is the U.S. National Stage ofInternational Application No. PCT/DK2009/050048, filed on Feb. 27, 2009,published in English, which claims the benefit of U.S. ProvisionalApplication No. 61/032,495, filed on Feb. 29, 2008, U.S. ProvisionalApplication No. 61/045,416, filed on Apr. 16, 2008 and U.S. ProvisionalApplication No. 61/142,678, filed on Jan. 6, 2009 and claims priorityunder 35 U.S.C. §119 or 365 to Denmark, Application No. PA 2008 00309DK, filed on Feb. 29, 2008, PA 2008 00556 DK, filed on Apr. 16, 2008 andPA 2009 00029 DK, filed Jan. 6, 2009. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to a device for promoting hemostasisand/or wound healing as well as to methods for making or using such adevice. The device comprises one or more bioactive compounds forpromoting hemostasis and/or wound healing. Said bioactive compounds arepreferably printed onto the surface of the device. The surface of thedevice can be the surface of a matrix of the device, such as the surfaceof a sponge. The invention further relates to a kit of parts comprisingsaid device for promotion of hemostasis and/or wound healing and acontainer for storage and/or preparation of said device.

BACKGROUND OF INVENTION

The present invention relates to an improved device for promotinghemostasis and/or wound healing, and an improved method for making saiddevice.

WO 2003/004072 discloses a method for coating a medical appliance, suchas a stent, with a bubblejet printing head. The coating may comprisepharmaceutically active compounds and may e.g. be in the form of apolymer with a suspended drug or a non-thrombogenic agent.

Xu et al (Biomaterials Vol. 27, 2006, p. 3580-3588) discloses use ofalternate inkjet printing of NT2 cells and fibrin gels (formed by thealternate printing of fibrinogen and thrombin), to create 3D cellularstructures consisting of layers of neural cells.

U.S. Pat. No. 6,361,551 and U.S. Pat. No. 6,454,787 both relate tomethods for depositing thrombin in solution or powder onto a hemostaticdevice, such as a sponge comprising collagen. The method of depositingthrombin comprises spraying thrombin in powder form onto the hemostaticdevice, or coating the device with a thrombin solution and subsequentlydrying the device of the invention by lyophilization or by conventionalmeans.

U.S. Pat. No. 4,752,466 is directed to a thrombin aerosol. Thrombin isdelivered in dry powdered form from a valve-actuated pressurizedpropellant-containing aerosol container. The thrombin has beenlyophilized from an aqueous solution also comprising athrombin-compatible synthetic polymer.

U.S. Pat. No. 6,472,162 and U.S. Pat. No. 7,056,722 both concern athrombin-solution without particles. The particles have been removed byfiltration so as to allow using the thrombin-solution as a spray.

U.S. Pat. No. 6,461,325 relates to a device for delivering fibrin andforming fibrin on a surface. The device delivers volumetric quantitiesof a first and a second biochemically reactive fluid comprising a sprayunit for separately atomizing the first and second biochemicallyreactive fluids into an aerosol. The first or second biochemicallyreactive fluids may comprise thrombin.

U.S. Pat. No. 6,113,948 relates to soluble microparticles comprisingthrombin or fibrinogen in free-flowing form. The microparticles can bemixed to give a dry powder to be used as a fibrin sealant that isactivated only at a wound site. The microparticles are produced byspray-drying.

US 2003/0175419 relates to methods for preparing biomimetic scaffolds byusing at least two bio-ink solutions. The bio-ink solutions can bedeposited individually or simultaneously. One bio-ink, which isstructural, can comprise thrombin, and inkjet technology can be employedto deposit the bio-inks of the biomimetic scaffold. Another form of abio-ink can comprise gelatin.

U.S. Pat. No. 6,416,739 discloses microcapsules comprising thrombin fortherapeutic use.

U.S. Pat. No. 6,649,162 is related to a hemostatic sponge based oncollagen and thrombin and a method for producing such a sponge as wellas a wound coverage containing said sponge. Thrombin is homogenouslydistributed in the sponge.

The prior art has not addressed sufficiently the issue of providing animproved matrix material, such as a sponge, comprising a pharmaceuticalcomposition comprising one or more agents or bioactive agents, such asthrombin; wherein said composition is initially in fluid or liquid formand applied onto the surface of said matrix material by printing thefluid or liquid composition in individual and discrete locations ontothe surface of the matrix material, thus obtaining an essentiallyuniform distribution of said fluid or liquid composition.

The printing technology according to the present invention allows for amore precise distribution of the composition onto the surface of thematrix material by applying an amount of the fluid or liquid compositionwhich preferably prevents swelling of the matrix material. The inventionavoids waste of fluid or liquid composition by exploiting the printingtechnology's more precise distribution of the fluid or liquidcomposition onto the matrix material. Compared to conventionaltechniques in the art, such as spraying, a more uniform distribution ofthe composition is also achieved.

SUMMARY OF THE INVENTION

In one aspect the present invention relates to a matrix materialcomprising a surface and a plurality of open and interconnected cells,wherein the surface of said matrix comprises a pharmaceuticalcomposition comprising one or more bioactive agents, such as thrombin,printed onto said surface of the matrix material at individual anddiscrete locations.

The invention further relates to a matrix material comprising apharmaceutical composition, such as thrombin, wherein said bioactiveagent is printed onto the surface of said matrix material.

The present invention further relates to a device comprising the matrixmaterial and a pharmaceutical composition as described above.

The present invention also relates to a kit of parts comprising thedevice described above and at least one additional component. In oneembodiment the kit of parts comprises a container e.g. for sterilestorage and/or preparation of said device. The container can be used toadd liquid to the matrix material prior to use.

In another aspect the present invention relates to a method for makingthe device described above comprising the steps of 1) providing a matrixmaterial and 2) printing a pharmaceutical composition in fluid or liquidform comprising one or more bioactive agents onto the surface of saidmatrix material e.g. at individual and discrete locations.

In yet another aspect the present invention relates to the use of thedevice or kit of parts described above to promote wound healing and/orhemostasis in an individual in need thereof.

The present invention is directed in another aspect to a method formanufacturing a matrix material comprising a pharmaceutical compositioncomprising one or more agents or bioactive agents deposited on theaccessible, external surface of said matrix material in discretelocations thereof, said method comprising the steps of

-   -   i. providing a matrix material,    -   ii. providing a printing device comprising a) one or more print        heads each comprising one or more nozzles, and b) one or more        reservoirs each comprising a pharmaceutical composition        comprising the one or more agents or bioactive agents in        solubilised form, or in the form of a suspension, wherein the        pharmaceutical composition is in fluid or liquid form,        -   said reservoir being connected to a degassing device and            operably connected with said one or more print heads so that            the fluid or liquid composition comprising the one or more            agents or bioactive agents can be diverted from said            reservoir to said one or more print heads,        -   actuating the one or more print heads and diverting from            each nozzle of each print head one or more droplets of the            fluid or liquid composition comprising the one or more            agents or bioactive agents to a predetermined and discrete            location of the accessible, external surface of said matrix            material,        -   wherein, preferably, each droplet of the fluid or liquid            composition contains a volume of liquid of less than about            100 nanoliters, such as less than about 80 nanoliters, for            example less than about 60 nanoliters, such as less than            about 40 nanoliters, for example less than about 20            nanoliters, such as less than about 10 nanoliters, for            example less than about 1 nanoliter, such as less than about            0.8 nanoliters, for example less than about 0.6 nanoliters,            such as less than about 0.4 nanoliters, for example less            than about 0.2 nanoliters, such as less than about 0.1            nanoliters, for example less than about 0.08 nanoliters,            such as less than about 0.06 nanoliters, for example less            than about 0.04 nanoliters, such as less than about 0.02            nanoliters, for example less than about 0.015 nanoliters,            such as less than about 0.010 nanoliters, for example less            than about 0.005 nanoliters, such as less than about 0.004            nanoliters, for example less than about 0.002 nanoliters,            such as less than about 0.001 nanoliters,        -   wherein the distance covered by each droplet of fluid or            liquid composition comprising the one or more agents or            bioactive agents from the point of departure of each nozzle            of each printing head to the point of impacting the            accessible, external surface of the matrix material at a            predetermined and discrete location thereof, is essentially            the shortest possible distance, such as essentially the            shortest distance defined by a diversion of droplet(s) from            each nozzle head, which is the distance which is essentially            perpendicular to the accessible, external surface of the            matrix at the predetermined and discrete position of the            surface where a given droplet impacts the matrix material,        -   wherein, preferably, the distance from each nozzle head to            the predetermined and discrete location to be impacted, at            the time of actuating the nozzle head and initialising the            diversion of said droplet(s) of liquid composition            comprising the one or more solubilised, bioactive agents            from the nozzle head to a given, predetermined and discrete            location, is essentially similar for each droplet of the            fluid or liquid composition and is less than about 4            millimeters, such as less than about 3.5 millimeters, for            example less than about 3 millimeters, such as less than            about 2.5 millimeters, for example less than about 2            millimeters, such as less than about 1.5 millimeters, for            example less than about 1.2 millimeters, such as less than            about 1.0 millimeters, for example less than about 0.8            millimeters, such as less than about 0.6 millimeters, for            example less than about 0.4 millimeters, such as less than            about 0.2 millimeters, for example less than about 0.1            millimeters,        -   wherein, preferably, the liquid portion of each droplet of            the composition comprising the one or more solubilised            agents or bioactive agents evaporates essentially on            impacting the accessible, external surface of the matrix            material, wherein said evaporation is determined at least by            the kinetic energy of the liquid of the droplet, including            the temperature of the liquid of the droplet, the            temperature of the matrix material and the temperature of            the environment in which the impacting of the droplet and            the matrix material takes place,        -   wherein, preferably, said evaporation of said liquid part of            said droplets of the composition comprising the one or more            solubilised agents or bioactive agents results in            essentially no swelling of the matrix material at the            predetermined and discrete locations of the accessible,            external surface of the matrix which are impacted by the            droplets of the composition comprising the one or more            solubilised, bioactive agents,        -   wherein, preferably, said evaporation and/or said            essentially no swelling of the matrix material results in            the provision of a matrix material comprising a solid            composition comprising one or more agents or bioactive            agents deposited in solid form on the accessible, external            surface of said matrix material in discrete locations            thereof,        -   wherein, preferably, the accessible and external surface of            said matrix material has essentially the same            physico-chemical properties before being impacted and after            being impacted with the droplets of the composition            comprising the one or more solubilised agents or bioactive            agents.

The one or more bioactive agents can be thrombin or thrombin incombination with fibrinogen, or thrombin and fibrinogen in combinationwith Factor XIII, or thrombin and fibrinogen and Factor XIII incombination with tranexamic acid.

The one or more agents or bioactive agents may be comprised in the samefluid or liquid composition contained in the same reservoir and expelledfrom the same print head comprising one or more nozzles, or the one ormore bioactive agents may be comprised in separate fluid or liquidcompositions contained in separate reservoirs and expelled from separateprint heads each comprising one or more nozzles or expelled fromdifferent channels of the same print head.

There is also provided a printing device comprising a) one or more printheads each comprising one or more nozzles, and b) one or more reservoirseach comprising a fluid or liquid composition comprising the one or morebioactive agents in solubilised form, such as the bioactive agents andcombinations thereof cited herein immediately above, wherein saidreservoir is connected to a degassing device and operably connected withsaid one or more print heads so that the liquid composition comprisingthe one or more solubilised, bioactive agents can be diverted from saidreservoir to said one or more print heads and released from said printheads as droplets of a predetermined volume upon actuation of thenozzles of said print heads.

In one embodiment, two or more fluid or liquid compositions eachcomprising one or more agents or bioactive agents may be imprinted atthe same or different discrete positions on the surface of said matrixmaterial.

The two or more pharmaceutical compositions initially in fluid or liquidform may each comprise one or more bioactive agents which may bethrombin or thrombin in combination with fibrinogen, or thrombin andfibrinogen in combination with Factor XIII, or thrombin and fibrinogenand Factor XIII in combination with tranexamic acid.

It is understood, that printing onto a surface of a matrix material maycomprise printing on the surface of any side of the matrix material.Thus, all or some of the planes of the matrix material may be imprinted.In one embodiment, the matrix material is a cube comprising six (6)planes, in which one or more planes are imprinted, such as 1 plane, forexample 2 planes, such as 3 planes, for example 4 planes, such as 5planes, for example 6 planes.

In a further aspect there is provided a composition comprising eitherthrombin, or thrombin in combination with fibrinogen, or thrombin andfibrinogen in combination with Factor XIII, or thrombin and fibrinogenand Factor XIII in combination with tranexamic acid, wherein saidcomposition further comprises a viscosity modulating agent andoptionally further a surfactant, wherein said composition preferably hasa cps (centipoise) of at least 4 cps, such as at least 6 cps, forexample at least 8 cps, such as at least 10 cps, for example at least 12cps, and preferably less than 100 cps, such as less than 80 cps, forexample less than 60 cps, for example less than 40 cps, such as lessthan 20 cps, for example less than 15 cps.

In a further embodiment there is provided a composition comprisingeither thrombin, or thrombin in combination with fibrinogen, or thrombinand fibrinogen in combination with Factor XIII, or thrombin andfibrinogen and Factor XIII in combination with tranexamic acid, whereinsaid composition preferably further comprises a viscosity modulatingagent and optionally further a surfactant, wherein said compositionpreferably has a surface tension of between 0.020 to 0.050 N/m; forexample 0.020-0.022 N/m, such as 0.022-0.024 N/m, for example0.024-0.026 N/m, such as 0.026-0.028 N/m, for example 0.028-0.030 N/m,such as 0.030-0.032 N/m, for example 0.032-0.034 N/m, such as0.034-0.036 N/m, for example 0.036-0.038 N/m, such as 0.038-0.040 N/m,for example 0.040-0.042 N/m, such as 0.042-0.044 N/m, for example0.044-0.046 N/m, such as 0.046-0.048 N/m, for example 0.048-0.050 N/m.

In another aspect the present invention relates to a matrix materialcomprising a surface and a plurality of open and interconnected cells,wherein the surface of said matrix is printed with thrombin inindividual and discrete locations. It has been found that the matrixprinted with thrombin is surprisingly sticky when it e.g. is used forone or more dry applications. Traditionally, a hemostatic compositionhas comprised a mixture of thrombin and fibrinogen, which leads togeneration of fibrin and a sticky effect. The present invention relatesin one embodiment to a sticky pharmaceutical composition printed onto amatrix, where the pharmaceutical composition does not comprise fibrinand/or fibrinogen.

The sticky effect of the pharmaceutical composition on the matrix isobserved by printing of thrombin in the range from 0.5 IU/cm² to 50IU/cm², such as from 0.5 IU/cm² to 1 IU/cm², for example from 1 IU/cm²to 2 IU/cm², such as from 2 IU/cm² to 3 IU/cm², for example from 3IU/cm² to 4 IU/cm², such as from 4 IU/cm² to 5 IU/cm², for example from5 IU/cm² to 6 IU/cm², such as from 6 IU/cm² to 7 IU/cm², for examplefrom 7 IU/cm² to 8 IU/cm², such as from 8 IU/cm² to 9 IU/cm², forexample from 9 IU/cm² to 10 IU/cm², such as from 10 IU/cm² to 11 IU/cm²,for example from 11 IU/cm² to 12 IU/cm²,

such as from 12 IU/cm² to 13 IU/cm², for example from 13 IU/cm² to 14IU/cm², such as from 14 IU/cm² to 15 IU/cm², for example from 15 IU/cm²to 16 IU/cm², such as from 16 IU/cm² to 17 IU/cm², for example from 17IU/cm² to 18 IU/cm², such as from 18 IU/cm² to 19 IU/cm², for examplefrom 19 IU/cm² to 20 IU/cm², such as from 20 IU/cm² to 21 IU/cm², forexample from 21 IU/cm² to 22 IU/cm², such as from 22 IU/cm² to 23IU/cm², for example from 23 IU/cm² to 24 IU/cm², such as from 24 IU/cm²to 25 IU/cm², for example from 25 IU/cm² to 26 IU/cm², such as from 26IU/cm² to 27 IU/cm², for example from 27 IU/cm² to 28 IU/cm², such asfrom 28 IU/cm² to 30 IU/cm², for example from 30 IU/cm² to 32 IU/cm²,such as from 32 IU/cm² to 34 IU/cm², for example from 34 IU/cm² to 36IU/cm², such as from 36 IU/cm² to 38 IU/cm², for example from 38 IU/cm²to 40 IU/cm², such as from 40 IU/cm² to 42 IU/cm², for example from 42IU/cm² to 44 IU/cm², such as from 44 IU/cm² to 46 IU/cm², for examplefrom 46 IU/cm² to 48 IU/cm², such as from 48 IU/cm² to 50 IU/cm².

In one preferred embodiment the amount of thrombin printed onto thematrix is in the range from 0.5 IU/cm² to 50 IU/cm², such as 1 IU/cm²,for example 2 IU/cm², such as 3 IU/cm², for example 4 IU/cm², such as 5IU/cm², for example 6 IU/cm², such as 7 IU/cm², for example 8 IU/cm²,such as 9 IU/cm², for example 10 IU/cm², such as 12 IU/cm², for example14 IU/cm², such as 16 IU/cm², for example 18 IU/cm², such as 20 IU/cm²,for example 22 IU/cm², such as 24 IU/cm², for example 26 IU/cm², such as28 IU/cm², for example 30 IU/cm², such as 32 IU/cm², for example 34IU/cm², such as 36 IU/cm², for example 38 IU/cm², such as 40 IU/cm², forexample 42 IU/cm², such as 44 IU/cm², for example 46 IU/cm², such as 48IU/cm², for example 50 IU/cm² e.g. to obtain a sticky effect for one ormore dry applications.

It has surprisingly been demonstrated that the sticky effect of thrombinon the matrix material is observed only when thrombin is printed ontosaid matrix material in accordance with the methods of the presentinvention. Spraying of thrombin onto the matrix material does not resultin a sticky effect.

In one embodiment the printing of thrombin onto a matrix materialresults after dry application in a stickiness exemplified by requirementof an amount of tension force in Newtons (1 g mass exerts. 9.81N) neededto pull a 2 cm² matrix from the skin is in the piconewton range,nanonewton range, micronewton range or in the millinewton range.

In another embodiment the printing of thrombin onto a matrix materialresults after dry application in a stickiness exemplified by requirementof an amount of tension force in Newtons (1 g mass exerts. 9.81N) neededto pull a 2 cm² matrix from the skin of is more than 0.001 Newton, suchas more than 0.01 Newton, for example 0.1 Newton, such as more than 0.5Newton, for example 1 Newton, such as more than 10 Newton, for example50 Newton, such as more than 100 Newton, for example 250 Newton, such asmore than 500 Newton, for example 1,000 Newton.

A surprising hemostatic effect has been demonstrated for a matrixprinted with a relatively low dose of thrombin for use in one or moredry applications.

In one further embodiment, any matrix material, such as a matrixmaterial printed or otherwise coated with a pharmaceutical compositioncomprising one or more bioactive agents, for example thrombin, isprovided in a container suitable for storing and preparing said matrixsealed from an external environment.

Storage of the matrix material in the container according to the presentinvention provides a sterile environment, and preparation of the matrixin the container may include the addition to the container of a suitableamount of any pharmaceutically acceptable liquid to moisten the matrixadequately.

Said container provides a means for easier addition of an appropriateand predetermined amount of liquid to the matrix, and it follows thatthe matrix will not be drained with excessive amounts of liquid toreduce the potential disadvantage of detachment of the pharmaceuticalcomposition from the matrix into the excess liquid, and furthermore themoistened matrix material is easier to handle and apply to a wound orsite of bleeding when not being excessively moistened. The container isvery stable and hence simplifies storage of prepared product on unevensurfaces.

DEFINITIONS

IU: In pharmacology, the International Unit or IU is a unit ofmeasurement for the amount of a substance, based on measured biologicalactivity or effect. The precise definition of one IU differs fromsubstance to substance and is established by international agreement foreach substance. There is no equivalence among different substances; forinstance, one IU of vitamin E does not contain the same number ofmilligrams as one IU of vitamin A. To define an IU of a substance, theCommittee on Biological Standardization of the World Health Organizationprovides a reference preparation of the substance, arbitrarily sets thenumber of IUs contained in that preparation, and specifies a biologicalprocedure to compare other preparations of that substance to thereference preparation. The goal in setting the standard is thatdifferent preparations with the same biological effect will contain thesame number of IUs.

Human thrombin activity is expressed in international units (IU)obtained by comparison towards the current WHO International Standard,using fibrinogen as substrate. The current WHO International Standard isnamed WHO 2nd International Standard for Thrombin 01/580 (In US: USFDA/CBER Thrombin Standard Lot K), and contains 110 IU by definition.

A degassing device is any device or structure used for alleviation ofgaseous build-up in a liquid comprised in a reservoir.

The term “Sticky” as used herein means that the substance has theproperty of adhering to or sticking to a surface. Stickiness can bemeasures as an adhesive force. Five mechanisms have been proposed toexplain why one material sticks to another: 1) Mechanical adhesion:Adhesive materials fill the voids or pores of the surfaces and holdsurfaces together by interlocking. Sewing forms a large scale mechanicalbond, velcro forms one on a medium scale, and some textile adhesivesform one at a small scale. This is similar to surface tension. 2)Chemical adhesion: Two materials may form a compound at the join. Thestrongest joins are where atoms of the two materials swap (ionicbonding) or share (covalent bonding) outer electrons. A weaker bond isformed if oxygen, nitrogen or fluorine atoms of the two materials sharea hydrogen nucleus (hydrogen bonding). 3) Dispersive adhesion: Indispersive adhesion, also known as adsorption, two materials are heldtogether by van der Waals forces: the attraction between two molecules,each of which has regions of positive and negative charge. In the simplecase, such molecules are therefore polar with respect to average chargedensity, although in larger or more complex molecules, there may bemultiple “poles” or regions of greater positive or negative charge.These positive and negative poles may be a permanent property of amolecule (Keesom forces) or a transient effect which can occur in anymolecule, as the random movement of electrons within the molecules mayresult in a temporary concentration of electrons in one region (Londonforces). 4) Electrostatic adhesion: Some conducting materials may passelectrons to form a difference in electrical charge at the join. Thisresults in a structure similar to a capacitor and creates an attractiveelectrostatic force between the materials. 5) Diffusive adhesion: Somematerials may merge at the joint by diffusion. This may occur when themolecules of both materials are mobile and soluble in each other. Thiswould be particularly effective with polymer chains where one end of themolecule diffuses into the other material. It is also the mechanisminvolved in sintering. When metal or ceramic powders are pressedtogether and heated, atoms diffuse from one particle to the next. Thisjoins the particles into one. The strength of the adhesion between twomaterials depends on which of the above mechanisms occur between the twomaterials, and the surface area over which the two materials contact.Materials that wet against each other tend to have a larger contact areathan those that do not. Wetting depends on the surface energy of thematerials.

“Stickiness” or “Adhesive force” can be measured by by one of themethods described in U.S. Pat. No. 4,194,392, US 20060282138 or U.S.Pat. No. 6,584,858. Stickiness in scientific terms is called adhesion.Adhesion is measured in terms of adhesive force in Newtons (N). Thehigher the adhesive force, the higher will be the number of Newtonsrequired to peel one object from the other.

“Hemostasis” is a term that refer to the physiologic process wherebybleeding is halted. It consists of multiple steps including 1)vasoconstriction to minimize vessel lumen diameter and slow bleeding, 2)platelet aggregation, 3) coagulation and 4) fibrinolysis whereby theblood clot is degraded.

Hemostatic agents are used herein interchangeably with the termsthrombogenic, thrombotic and pro-coagulant agents. Hemostatic agents areagents that induce blood clotting or hemostasis.

The term “blood clotting cascade” or “blood coagulation cascade” is partof secondary hemostasis and refers to the multi-step process wherebyblood and vessel components react to stimuli by the enzymatic activationof coagulation factors sequentially, ultimately resulting in theformation of a solid blood clot comprising fibrin gel and platelets.

Vasoconstriction is a narrowing of the blood vessels resulting fromcontracting of the muscular wall of the vessels. When blood vesselsconstrict, the flow of blood is restricted or slowed. Factors causingvasoconstriction are called vasoconstrictor, also vasopressors or simplypressors. Vasoconstriction is mostly the result of increasedintracellular concentration of calcium (Ca²⁺). However, specificmechanisms for generating an increased intracellular concentration ofcalcium depend on the vasoconstrictor. In any case, this calcium resultsin contraction of smooth muscle resulting in a constriction of thevessel.

“Thrombosis” refers to thrombus formation, and a “thrombus” is a bloodclot i.e. the final step in the blood coagulation cascade of hemostasis.A thrombus is physiologic in cases of injury, but pathologic in case ofthrombosis thus occurring in an intact blood vessel.

An “embolism” occurs when an object (the embolus, plural emboli)migrates from one part of the body (through circulation) and cause(s) ablockage (occlusion) of a blood vessel in another part of the body.

A “Bioactive agent” is any agent, drug, compound, composition of matteror mixture which provides some pharmacologic, often beneficial, effectthat can be demonstrated in-vivo or in vitro. As used herein, this termfurther includes any physiologically or pharmacologically activesubstance that produces a localized or systemic effect in an individual.Further examples of bioactive agents include, but are not limited to,agents comprising or consisting of an oligosaccharide, agents comprisingor consisting of a polysaccharide, agents comprising or consisting of anoptionally glycosylated peptide, agents comprising or consisting of anoptionally glycosylated polypeptide, agents comprising or consisting ofan oligonucleotide, agents comprising or consisting of a polynucleotide,agents comprising or consisting of a lipid, agents comprising orconsisting of a fatty acid, agents comprising or consisting of a fattyacid ester and agents comprising or consisting of secondary metabolites.It may be used either prophylactically, therapeutically, in connectionwith treatment of an individual, such as a human or any other animal.

The terms “drug,” “medicament,” or “bioactive substance/agent” (i.e.,biologically active substance/agent) as used herein include,biologically, physiologically, or pharmacologically active substancesthat act locally or systemically in the human or animal body.

The terms “treating”, “treatment” and “therapy” as used herein referequally to curative therapy, prophylactic or preventative therapy andameliorating therapy. The term includes an approach for obtainingbeneficial or desired physiological results, which may be establishedclinically. For purposes of this invention, beneficial or desiredclinical results include, but are not limited to, alleviation ofsymptoms, diminishment of extent of disease, stabilized (i.e., notworsening) condition, delay or slowing of progression or worsening ofcondition/symptoms, amelioration or palliation of the condition orsymptoms, and remission (whether partial or total), whether detectableor undetectable. The term “palliation”, and variations thereof, as usedherein, means that the extent and/or undesirable manifestations of aphysiological condition or symptom are lessened and/or time course ofthe progression is slowed or lengthened, as compared to notadministering compositions of the present invention.

A “treatment effect” or “therapeutic effect” is manifested if there is achange in the condition being treated, as measured by the criteriaconstituting the definition of the teams “treating” and “treatment.”There is a “change” in the condition being treated if there is at least5% improvement, preferably 10% improvement, more preferably at least25%, even more preferably at least 50%, such as at least 75%, and mostpreferably at least 100% improvement. The change can be based onimprovements in the severity of the treated condition in an individual,or on a difference in the frequency of improved conditions inpopulations of individuals with and without treatment with the bioactiveagent, or with the bioactive agent in combination with a pharmaceuticalcomposition of the present invention.

“Pharmacologically effective amount”, “pharmaceutically effectiveamount” or “physiologically effective amount” of a “bioactive agent” isthe amount of an active agent present in a pharmaceutical composition asdescribed herein that is needed to provide a desired level of activeagent in the bloodstream or at the site of action in an individual(e.g., the lungs, the gastric system, the colorectal system, prostate,etc.) to be treated to give an anticipated physiological response whensuch composition is administered. The precise amount will depend uponnumerous factors, e.g., the active agent, the activity of thecomposition, the delivery device employed, the physical characteristicsof the composition, intended patient use (i.e., the number of dosesadministered per day), patient considerations, and the like, and canreadily be determined by one skilled in the art, based upon theinformation provided herein. An “effective amount” of a bioactive agentcan be administered in one administration, or through multipleadministrations of an amount that total an effective amount, preferablywithin a 24-hour period. It can be determined using standard clinicalprocedures for determining appropriate amounts and timing ofadministration. It is understood that the “effective amount” can be theresult of empirical and/or individualized (case-by-case) determinationon the part of the treating health care professional and/or individual.

The terms “enhancing” and “improving” a beneficial effect, andvariations thereof, as used herein, refers to the therapeutic effect ofthe bioactive agent against placebo, or an increase in the therapeuticeffect of a state-of-the-art medical treatment above that normallyobtained when a pharmaceutical composition is administered without thebioactive agent of this invention. “An increase in the therapeuticeffects” is manifested when there is an acceleration and/or increase inintensity and/or extent of the therapeutic effects obtained as a resultof administering the bioactive agent(s). It also includes extension ofthe longevity of therapeutic benefits. It can also manifest where alower amount of the pharmaceutical composition is required to obtain thesame benefits and/or effects when it is co-administered with bioactiveagent(s) provided by the present invention as compared to theadministration in a higher amount of the pharmaceutical composition inthe absence of bioactive agent. The enhancing effect preferably, but notnecessarily, results in treatment of acute symptoms for which thepharmaceutical composition alone is not effective or is less effectivetherapeutically. Enhancement is achieved when there is at least a 5%increase in the therapeutic effects, such as at least 10% increase inthe therapeutic effects when a bioactive agent of the present inventionis co-administered with a pharmaceutical composition compared withadministration of the pharmaceutical composition alone. Preferably theincrease is at least 25%, more preferably at least 50%, even morepreferably at least 75%, most preferably at least 100%.

“Co-administering” or “co-administration” of bioactive agent(s), orbioactive agents and state-of-the-art medicaments, as used herein,refers to the administration of one or more bioactive agents of thepresent invention, or administration of one or more bioactive agents ofthe present invention and a state-of-the-art pharmaceutical compositionwithin a certain time period. The time period is preferably less than 72hours, such as 48 hours, for example less than 24 hours, such as lessthan 12 hours, for example less than 6 hours, such as less than 3 hours.However, these terms also mean that the bioactive agent and atherapeutic composition can be administered together.

The term “Individual” refers to vertebrates, particular members of themammalian species, and includes, but is not limited to domestic animals,such as cattle, horses, pigs, sheep, mink, dogs, cats, mice, guineapigs, rabbits, rats; sports animals, such as horses, poly ponies, dogs,camels, and primates, including humans.

The term “Kit of parts” as used in the present invention provides thematrix material according to the present invention, such as a matrixmaterial printed with thrombin, and at least one additional component.The additional component may in one embodiment be a container asspecified herein. Accordingly, in one embodiment the kit comprisesinstructions for use of the matrix material.

‘Wound’: The term refers to cuts, incisions, abrasions, lacerations,amputations, burns induced by heat, ionizing radiation, ultravioletradiation including sunlight, electricity, or chemical substances aswell as to other forms of lesions such as ulcers, pressure sores andbedsores.

“Partial thickness wound” refers to wounds that encompass Grades I-III;examples of partial thickness wounds include burn wounds, pressuresores, venous stasis ulcers, and diabetic ulcers.

“Deep wound” is meant to include both Grade III and Grade IV wounds. Thepresent invention contemplates treating all wound types, including deepwounds and chronic wounds.

“Chronic wound” refers to a wound that has not healed within 30 days.“Alginate” refers to a linear co-polymer with homopolymeric blocks of(1-4)-linked β-D-mannuronate (M) and its C-5 epimer α-L-guluronate (G)residues, respectively, covalently linked together in differentsequences or blocks.

“Hydrocolloid” refers to a colloid system in which the colloid-formingcomponents are dispersed in water, but not cross-linked. A colloidsystem is a system or mixture in which two substances are interspersedbetween each other. A hydrocolloid has colloid particles spreadthroughout water and depending on the quantity of water available cantake on different states, e.g: gel-like consistency or a sol (liquid).Hydrocolloids can be either irreversible (single state) or reversible.Examples include carrageenan, gelatin and pectin.

“Wound healing-promoting agent” is any agent capable of accelerating thewound healing process.

“Promote wound healing” and “accelerate wound healing,” and similarphrases, refer to either the induction of the formation of granulationtissue of wound contraction and/or the induction of epithelialization(i.e., the generation of new cells in the epithelium). Wound healing isconveniently measured by decreasing wound area.

A ‘hydrogel’ is a network of polymer chains that are water-insoluble,sometimes found as a colloidal gel in which water is the dispersionmedium. Hydrogels are superabsorbent (they can contain over 99% water)natural or synthetic polymers. Hydrogels possess also a degree offlexibility very similar to natural tissue, due to their significantwater content.

A ‘polymer’ is a substance composed of molecules with large molecularmass composed of repeating structural units, or monomers, connected bycovalent chemical bonds. The word is derived from the Greek, polu,“many”; and meros, “part”. Well known examples of polymers includeplastics, DNA and proteins. A simple example is polypropylene. While theterm “polymer” in popular usage suggests “plastic”, polymers comprise alarge class of natural and synthetic materials with a variety ofproperties and purposes. Natural polymer materials include shellac,amber and cellulose, which is the main constituent of wood and paper.There are three main classes of ‘biopolymers’: polysaccharides,polypeptides (proteins), and polynucleotides. A heteropolymer orcopolymer is a polymer derived from two (or more) monomeric species, asopposed to a homopolymer where only one monomer is used.

‘Polysaccharides’ are relatively complex carbohydrates. They arepolymers made up of many monosaccharides joined together by glycosidicbonds. They are therefore very large, often branched, macromolecules.They tend to be amorphous, insoluble in water, and have no sweet taste.When all the monosaccharides in a polysaccharide are the same type thepolysaccharide is called a homopolysaccharide, but when more than onetype of monosaccharide is present they are called heteropolysaccharides.Examples include storage polysaccharides such as starch and glycogen andstructural polysaccharides such as cellulose and chitin. Polysaccharideshave a general formula of C_(n)(H₂O)_(n-1) where n is usually a largenumber between 200 and 2500. Considering that the repeating units in thepolymer backbone are often six-carbon monosaccharides, the generalformula can also be represented as (C₆H₁₀O₅)_(n) where n={40 . . .3000}.

‘Peptides’ are short polymers formed from the linking, in a definedorder, of α-amino acids. The link between one amino acid residue and thenext is known as an amide bond or a peptide bond. Proteins are‘polypeptide’ molecules (or consist of multiple polypeptide subunits).The distinction is that peptides are short and polypeptides/proteins arelong.

‘Cross-links’ are bonds that link one polymer chain to another. They canbe covalent bonds or ionic bonds. “Polymer chains” can refer tosynthetic polymers or natural polymers (such as proteins). When the term“cross-linking” is used in the synthetic polymer science field, itusually refers to the use of cross-links to promote a difference in thepolymers' physical properties. When “crosslinking” is used in thebiological milieu, it can be in reference to its use as a probe to linkproteins together to check protein-protein interactions, as well asother creative cross-linking methodologies.

A ‘drop’ or ‘droplet’ is a small volume of liquid or fluid, boundedcompletely or almost completely by free surfaces. The volume of a dropis not well-defined: it depends on the device and technique used toproduce the drop and on the physical properties of the fluid. A dropletaccording to the present invention has been defined regarding sizeelsewhere (pico to nano litre range).

A ‘Surface’ according to the present invention refers to the outer layeror outer part of a matrix material, which is the part that may beaccessible for printing and thus do not comprise the inner andinaccessible part of the material. By accessible is meant accessible fora printing technique according to the present invention. The surface insuch a setting may be the outer few millimeters of the material, and maybe uneven or porous. The surface in one setting may be one-dimensional.

‘Printing’ according to the present invention refers to the depositionof a fluid or liquid composition onto the surface of a matrix material,in which the fluid or liquid composition in the form of droplet(s) makescontact with the surface of the matrix material of interest, and thesolvent or liquid component of the droplet subsequently evaporates toleave a solid or dry composition on the surface of the printed matrixmaterial. The small volume of fluid or liquid composition and the rapidevaporation of the solvent or liquid component means that essentially noswelling of the matrix material will occur. The printing technologyshould be distinguished from technologies such as ‘spraying’, ‘dipping’or ‘coating’, as the printing method is more precise, morecost-effective, and results in a more uniform distribution of thecomposition (hence, the agent or bioactive agent of the composition) atdiscrete positions on the surface of a matrix. Printing furthermoreoccur perpendicular to the surface of the substrate, making the distancebetween nozzles of the print head and the surface of the substrateessentially identical for all droplets of the fluid or liquidcomposition. Further, the distance traversed by each droplet of thecomposition is in general shorter for printing than for spraying.Printing and jetting are used interchangeably herein. One means ofprinting involves the ‘inkjet’ printing technology.

‘Perpendicular to the surface’ is understood in that the dropletexpelled from the nozzle will contact the surface of the matrix materialessentially directly below the nozzle. Thus, the angle between thestraight line of the distance that the droplet traverses from the nozzleand the nozzle of the print head will be essentially 90°. Deviations ofup to about 5% from a 90° angle can be tolerated.

“Sterile storage” means that a compartment, container or box used forstorage of the matrix material should facilitate a micro-environmentmade essentially free of infectious microorganisms at least to a degreewhich satisfies the intended use of the matrix material. To obtainsterility, a sterile matrix material could either be packed understerile conditions, or a matrix material could be sealed within thepackaging and subsequently be sterilised by methods known in the art,e.g. by radiation.

A pharmaceutical composition as used herein is a composition comprisingone or more agents or bioactive agents, either in solid or dry form(after printing and evaporation) or in fluid or liquid form (prior toand during printing).

A fluid or liquid composition is a pharmaceutical composition in fluidor liquid form, used for printing onto the surface of a matrix material.

A solid composition is a pharmaceutical composition which was initiallyin fluid or liquid form, which has been printed onto the surface of amatrix material, and wherein the liquid portion or solvent component ofeach droplet of the fluid or liquid composition comprising the one ormore solubilised agents or bioactive agents has evaporated essentiallyon impacting the surface of the matrix material.

DESCRIPTION OF DRAWINGS

FIGS. 1A and 1B illustrates the modes of A) spraying and B) printing, toillustrate features of each method for depositing a fluid or liquidcomposition comprising one or more bioactive agents onto a surface of amatrix material. Differences between the two modes of application arethus illustrated.

In FIG. 1A, spraying occurs in an angled manner whereby the distancefrom nozzle to surface of the matrix material varies for the dropletsfrom individual nozzles. Therefore, the composition will be deposited athigher density in the middle of the spray and a lower density at theedge of the spray, to make a concentration gradient. As shown in FIG.1B, printing occur perpendicular to the surface of the matrix material,whereby the distance from nozzle to surface of the matrix material isidentical for each droplet expelled form the nozzle. The depositedmaterial will therefore be uniformly distributed. The distance fromnozzle to surface of the matrix material is in general larger forspraying techniques than for printing techniques. The distance betweenthe nozzle of the print head and surface of the matrix material isdefined in the text. These features makes printing more precise andefficient than spraying, enabling printing in individual and discretelocations on the matrix material, and providing a uniform distributionof a smaller volume of the printer composition than that required byconventional techniques, such as spraying (please refer to text for moredetail on this subject).

FIGS. 2A and 2B illustrate a container without and with a a matrixmaterial, respectively. The bottom of the inner tray is marked (1), thesidewall is marked (2), the mark on the sidewall is marked (3), theinner tray notch is marked (4), the base is marked (5), the handle ismarked (6), the sealing surface for the lid is marked (7) and the lid ismarked (8).

FIGS. 3A and 3B illustrate a container containing a matrix material. Thebottom of the inner tray is marked (1), the sidewall is marked (2), themark on the sidewall is marked (3), the base is marked (5), the handleis marked (6), the sealing surface for the lid is marked (7) and the lidis marked (8).

FIG. 4 illustrates a preferred container for a matrix material termedTeacup100. The bottom of the inner tray is marked (1), the sidewall ismarked (2), the mark on the sidewall is marked (3), the inner tray notchis marked (4), the base is marked (5), and the handle is marked (6). Thelength (200.4 mm) and width (130.35 mm) of the base is indicated.

FIG. 5 illustrates a preferred container for a matrix material termedTeacup50. The bottom of the inner tray is marked (1), the sidewall ismarked (2), the mark on the sidewall is marked (3), the inner tray notchis marked (4), the base is marked (5), and the handle is marked (6). Thelength (137.3 mm) and width (130.35 mm) of the base is indicated.

FIG. 6 illustrates a preferred container for a matrix material termedTeacup12-7. The bottom of the inner tray is marked (1), the sidewall ismarked (2), the mark on the sidewall is marked (3), the inner tray notchis marked (4), the base is marked (5), and the handle is marked (6). Thelength (97.4 mm) and width (130.35 mm) of the base is indicated.

FIGS. 7A and 7B illustrate the printing of two different fluid or liquidcompositions each comprising at least one agent or bioactive agent(composition A and composition B), wherein printing occurs at differentand discrete positions for each composition onto the surface of a matrixmaterial. The fluid or liquid compositions A and B may comprise agentsor bioactive agents which are not compatible when comprised in the samefluid or liquid composition, and the printing technology allows for saidincompatible agents or bioactive agents to be printed separately but inclose proximity to each other, for example in alternating positions onthe surface of a matrix material. FIG. 7A illustrates the printing oftwo different fluid or liquid compositions from a sideview; FIG. 7A is atopview of a matrix material which has been imprinted with compositionsA and B in alternating discrete positions on the surface of the matrixmaterial.

FIG. 8 shows the time to hemostasis using Surgiform™ in pig spleenmodel. The efficacy of Surgifoam™ with thrombin applied by ink-jetprinting was examined in a pig spleen model and compared to the standardwet use of Surgifoam™+thrombin. Results are medians+/−max/min. TheSurgifoam™ was either applied wet or dry. For the wet application 4 cm²Surgifoam™ was moistened in either 800 ul Saline, 800 ul standardthrombin solution at 1000 IU/ml (˜200 IU/cm²) or 800 ul low thrombinsolution at 100 IU/ml (˜20 IU/cm²). Standard use of thrombin withgelatin sponge today is 1000 IU/ml. For the dry application Surgifoam™alone or printed with 20, 10 or 5 IU/cm² was applied on the spleenwound. Each product was tested 3 or 4 times.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention are disclosed herein below with aview of disclosing both the present invention and equivalents thereofwhich are within reach of a skilled person having read the presentapplication.

Deposition of a Pharmaceutical Composition onto a Surface by Printing

The present invention in one embodiment relates to a medical devicecomprising a composition, such as a pharmaceutical composition, which isdeposited in discrete and individual positions onto the surface of thedevice, such as onto the surface of a matrix material of the device. Thedeposition of the composition is preferably achieved by printing thefluid or liquid composition onto the surface of the device, such as in amanner achieved by inkjet printing or any similar form of printingtechnology.

It follows that a fluid or liquid composition according to the presentinvention may be any liquid or gaseous composition, and covers anysolution, suspension and emulsion. In one embodiment, the fluid orliquid composition is a particulate composition, which may be liquid,gaseous, solid or dry. A particulate composition may be employed if thesize of the particles does not exceed the nozzle diameter which thecomposition exits from the print head (see below).

Printing the composition onto the surface of the device by using e.g.inkjet printing technologies does not involve a direct contact between aprinting head and the surface of the device. To position a drop byprinting is more precise and should be distinguished from e.g. sprayingor coating the composition onto the device, or by otherwise contactingthe device with the composition e.g. by contacting the device with thecomposition in any suitable fluid or liquid form, including dipping thedevice into a composition in liquid form.

Printing allows for a more uniform distribution of the composition.Further, the composition can be positioned at individual and discretelocations or positions on the surface of the matrix when using printingtechnology, thus dramatically increasing the precision of the depositedcomposition. Indeed, printing allows for a more uniform distribution ofa small volume of a liquid composition, consequently reducing theswelling of the matrix material onto which the composition is printed,applying a smaller and more precise amount of the bioactive agentcomprised in the composition, and reducing wastage of said liquidcomposition than conventional techniques such as spraying.

Further, with the printing technology, two or more separate compositionsbeing contained in separate reservoirs and being printed from separateprinting heads or expelled from different channels of the same printhead may each be printed onto discrete and non-overlapping positions ofthe same matrix material. This allows for printing in discrete and/oralternating positions onto the same matrix material of two or morecompositions each comprising one or more agents or bioactive agentswhich are incompatible when contained in the same liquid compositions.

Various suitable printing technologies are disclosed in more detailherein below.

Printing Technologies

Printing technologies may operate by propelling various size (mostlytiny) droplets of liquid, fluid or molten material onto a media. ‘Inkjetprinters’ or ‘bubblejet printers’ are the most common type of computerprinter for the general consumer due to their low cost, high quality ofoutput, capability of printing in vivid color, and ease of use. Printingtechnologies may be used to deposit materials directly on substrates ormatrixes. A piezoelectric printer is an example of a printing technologycapable of deposing materials onto a substrate. An advantage of thematerial deposition technique or printing technique is the precisionavailable with this technology, which may be required for someindustrial applications. Further, reduced amounts of material may beused, thus reducing costs by using expensive materials more efficientlyby placing material only where needed. This yields a more uniformdistribution on the surface of the matrix of the pharmaceuticalcomposition. The fluid or liquid composition to be printed (or ‘jetted’)must be compatible with the print head used and must have its viscosityas well as it surface tension within a specific range within operatingtemperature. The fluid to be printed may be e.g. a bio-ink, a fluid orliquid composition, such as a pharmaceutical composition, or a gaseouscomposition, and the fluid or liquid composition may contain one or moreagents or bioactive agent(s).

In one embodiment of the present invention, a method for depositingmaterial of a composition onto the surface of a substrate or matrixmaterial is disclosed. The material to be deposited is in a preferredembodiment printed onto the surface of the matrix material. Printing maycomprise ‘inkjet’ printing technologies or other printing technologies.The material to be printed may be a pharmaceutical composition, that inone embodiment comprises one or more or agents or bioactive agent(s). Inone embodiment, the bioactive agent is thrombin. In yet an embodiment,the matrix material is a gelatin-based sponge.

Inkjet Printing

There are three main technologies in use in contemporary inkjetprinters: thermal, piezoelectric, and continuous.

Thermal inkjets: Most consumer inkjet printers (Lexmark,Hewlett-Packard, Canon) use print cartridges with a series of tinyelectrically heated chambers constructed by photolithography. To producean image, the printer runs a pulse of current through the heatingelements causing a steam explosion in the chamber to form a bubble,which propels a droplet of ink or fluid onto the substrate (henceCanon's tradename of Bubblejet for its inkjets). The ink's or fluid'ssurface tension as well as the condensation and thus contraction of thevapor bubble, pulls a further charge of ink or fluid into the chamberthrough a narrow channel attached to an ink or fluid reservoir. Thebubblejet technology has been used for uniformly coatingpharmaceutically active compounds onto medical appliances such as astent, e.g. WO 2003/004072.

Piezoelectric inkjets: Most commercial and industrial inkjet printersuse a piezoelectric material in a fluid-filled chamber behind eachnozzle instead of a heating element. When a voltage is applied, thepiezoelectric material changes shape or size, which generates a pressurepulse in the fluid forcing a droplet from the nozzle. This isessentially the same mechanism as the thermal inkjet but generates thepressure pulse using a different physical principle. Piezoelectricinkjet allows a wider variety of fluids than thermal or continuousinkjet printers.

Piezoelectricity is the ability of some materials (notably crystals andcertain ceramics) to generate an electric potential in response toapplied mechanical stress. This may take the form of a separation ofelectric charge across the crystal lattice. If the material is notshort-circuited, the applied charge induces a voltage across thematerial. The word is derived from the Greek piezein, which means tosqueeze or press. The piezoelectric effect is reversible in thatmaterials exhibiting the direct piezoelectric effect (the production ofelectricity when stress is applied) also exhibit the conversepiezoelectric effect (the production of stress and/or strain when anelectric field is applied). For example, lead zirconate titanatecrystals will exhibit a maximum shape change of about 0.1% of theoriginal dimension. The effect finds useful applications such as theproduction and detection of sound, generation of high voltages,electronic frequency generation, microbalances, and ultra fine focusingof optical assemblies. It is also the basis of a number of scientificinstrumental techniques with atomic resolution, the scanning probemicroscopies.

Continuous inkjet: The continuous inkjet method is used commercially formarking and coding of products and packages. In continuous inkjettechnology, a high-pressure pump directs liquid from a reservoir througha gunbody and a microscopic nozzle, creating a continuous stream ofdroplets. A piezoelectric crystal creates an acoustic wave as itvibrates within the gunbody and causes the stream of liquid to breakinto droplets at regular intervals 64,000 to 165,000 drops per secondmay be achieved. The droplets are subjected to an electrostatic fieldcreated by a charging electrode as they form, the field varied accordingto the degree of drop deflection desired. This results in a controlled,variable electrostatic charge on each droplet. Charged droplets areseparated by one or more uncharged “guard droplets” to minimizeelectrostatic repulsion between neighboring droplets. The chargeddroplets pass through an electrostatic field and are directed(deflected) by electrostatic deflection plates to print on the receptormaterial (substrate), or allowed to continue on undeflected to acollection gutter for re-use. The more highly charged droplets aredeflected to a greater degree. Only a few percent of the droplets areactually used to print, the majority being recycled. One of itsadvantages is the very high velocity (−50 m/s) of the droplets, whichallows for a relatively long distance between print head and substrate.Another advantage is freedom from nozzle clogging as the jet is alwaysin use, therefore allowing volatile solvents such as ketones andalcohols to be employed, giving the fluid the ability to “bite” into thesubstrate and dry quickly. The system requires active solvent regulationin order to accommodate for solvent evaporation during the time offlight (time between nozzle ejection and gutter recycling) and from theventing process whereby air that is drawn into the gutter along with theunused drops is vented from the reservoir.

Print Heads and Nozzles of the Printing Device

The printing technology according to the present invention in oneembodiment employs one or more printing heads or print heads, whereineach printing head comprises one or more nozzles.

A nozzle is a mechanical device designed to control the characteristicsof a fluid flow as it exits (or enters) an enclosed chamber or pipe viaan orifice. A print head is the element of a printer that applies thefluid or liquid composition to the substrate or matrix material; thusbeing connected to one or more reservoirs comprising a fluid or liquidcomposition.

In one embodiment, one printing head with one nozzle is used. In anotherembodiment, one printing head with multiple individual printing nozzlesis used. In another embodiment, two or more printing heads each with onenozzle are used. In yet another embodiment, two or more printing headseach with multiple individual printing nozzles are used.

Each print head may be connected to one or more reservoir(s) comprisinga fluid or liquid composition. It follows, that the nozzles of any oneprint head may be connected via the same channels to the same reservoirthus ejecting the same fluid or liquid composition, or the nozzles ofany one print head may be connected via separate channels to separatereservoirs thus ejecting separate fluid or liquid compositions. In oneembodiment, a print head comprises 256 nozzles, composed of 4 times 64addressable channels which may be connected to four separate reservoirs.

The fluid or liquid composition will be expelled from the nozzle(s) ofthe print head(s) in the form of droplets or particles.

The nozzle may be any type of nozzle, and the print head may be any typeof print head. In one embodiment, the nozzle is a deformable hose thatis forced to eject droplets by punching the hose with a piston. Anexample of a printing system comprising such a nozzle is the PipeJet™dispensing technology of the BioSpot® systems (BioFluidix GmbH).

In one embodiment, the nozzles are actuated by a high-voltage firepulse. In one embodiment, the print head ejects droplets at a velocityin the range of 0.1-100 m/sec; such as 0.1-1 m/sec, for example 1-2msec, such as 2-3 msec, for example 3-4 m/sec, such as 4-5 m/sec, forexample 5-6 m/sec, such as 6-7 m/sec, for example 7-8 m/sec, such as 8-9m/sec, for example 9-10 m/sec, such as 10-15 m/sec, for example 15-20m/sec, such as 20-30 m/sec, for example 30-40 m/sec, such as 40-50m/sec, for example 50-60 m/sec, such as 60-70 m/sec, for example 70-80m/sec, such as 80-90 m/sec, for example 90-100 m/sec.

The nozzle diameter may be in the range of 1-1000 microns; such as 1-5microns, for example 5-10 microns, such as 10-20 microns, for example20-30 microns, such as 30-40 microns, for example 40-50 microns, such as50-60 microns, for example 60-70 microns, such as 70-80 microns, forexample 80-90 microns, such as 90-100 microns, for example 100-200microns, such as 200-300 microns, for example 300-400 microns, such as400-500 microns, for example 500-600 microns, such as 600-700 microns,for example 700-800 microns, such as 800-900 microns, for example900-1000 microns.

A print head may comprise any number of nozzles or addressable jets. Inone embodiment, one print head comprises 4 times 64 nozzles making atotal of 256 nozzles on one print head. Any number of nozzles per printhead may be employed, such as 4, 16, 32, 64, 128, 256, 512, 1024, 2048;or any number in the range of 1-50, 50-100, 100-150, 150-200, 200-250,250-300, 300-350, 350-400, 400-450, 450-500, 500-600, 600-700, 700-800,800-900, 900-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400,1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900, 1900-2000,2000-2500, 2500-3000, 3000-4000, 4000-5000, 5000-10,000 nozzles perprint head.

In one embodiment, one print head may comprise more than one independentpiezoelectric slices each with a number of addressable channels. Thenozzles may be arranged on the print head in any pattern, such as in asingle line or in multiple lines.

In one embodiment, the print head contains means for selecting whichnozzles to fire at which point in time, such as a serial-to-parallelconverter.

The printing head(s) of the printing system may move with respect to thesurface of the matrix material onto which a composition will bedeposited.

Distance Between the Nozzle(s) and the Surface

In one preferred embodiment of the invention, the nozzle(s) of theprinting head(s) and the surface of the substrate or matrix material arenot in direct liquid contact, but the distance between surface andnozzle is kept at a minimum.

In particular, the distance between the nozzle and the surface is lowerwhen using the printing technology than when spraying a composition ontoa surface which results in a very precise location of each droplet.

A print head of a printing device used for depositing or printing afluid or liquid composition deposits the fluid or liquid composition ina vertical manner onto a surface of a matrix material. The fluid orliquid composition in droplet form is thus transferred perpendicular tothe surface of the matrix material or substrate. Each droplet of thefluid or liquid composition thus traverses an essentially identicaldistance with an essentially identical velocity from the nozzle of theprint head to the surface of the matrix material. This greatly increasesthe precision of deposition, thus achieving a uniform distribution andreducing waste.

In one embodiment, the distance traversed by any droplet from the printhead or nozzle(s) to the surface of the matrix material is less than 10mm. The distance between the surface of the matrix material and theprint head or nozzle may be less than 0.01 mm, such as less than 0.02mm, for example less than 0.03 mm, such as less than 0.04 mm, forexample less than 0.05 mm, such as less than 0.06 mm, for example lessthan 0.07 mm, such as less than 0.08 mm, for example less than 0.09 mm,such as less than 0.1 mm, for example less than 0.2 mm, such as lessthan 0.3 mm, for example less than 0.4 mm, such as less than 0.5 mm, forexample less than 0.6 mm, such as less than 0.7 mm, for example lessthan 0.8 mm, such as less than 0.9 mm, for example less than 1.0 mm,such as less than 1.1 mm, for example less than 1.2 mm, such as lessthan 1.3 mm, for example less than 1.4 mm, such as less than 1.5 mm, forexample less than 1.6 mm, such as less than 1.7 mm, for example lessthan 1.8 mm, such as less than 1.9 mm, for example less than 2.0 mm,such as less than 2.1 mm, for example less than 2.2 mm, such as lessthan 2.3 mm, for example less than 2.4 mm, such as less than 2.5 mm, forexample less than 2.6 mm, such as less than 2.7 mm, for example lessthan 2.8 mm, such as less than 2.8 mm, for example less than 3.0 mm,such as less than 3.5 mm, for example less than 4.0 mm, such as lessthan 4.5 mm, for example less than 5.0 mm, such as less than 6.0 mm, forexample less than 7.0 mm, such as less than 8.0 mm, for example lessthan 9.0 mm, such as less than 10.0 mm. This is illustrated in FIG. 1B.

In another embodiment of the invention, the distance between the surfaceof the matrix material and the print head or nozzle(s) is in the range0.01 to 10.0 mm; for example 0.01-0.02 mm, such as 0.02-0.03, forexample 0.03-0.04, such as 0.04-0.05, for example 0.05-0.06, such as0.06-0.07, for example 0.07-0.08, such as 0.08-0.09, for example0.1-0.2, such as 0.2-0.3, for example 0.3-0.4, such as 0.4-0.5, forexample 0.5-0.6, such as 0.6-0.7, for example 0.7-0.8, such as 0.8-0.9,for example 0.9-1.0, such as 1.0-1.1, for example 1.1-1.2, such as1.2-1.3, for example 1.3-1.4, such as 1.4-1.5, for example 1.5-1.6, suchas 1.6-1.7, for example 1.7-1.8, such as 1.8-1.9, for example 1.9-2.0,such as 2.0-2.1, for example 2.1-2.2, such as 2.2-2.3, for example2.3-2.4, such as 2.4-2.5, for example 2.5-2.6, such as 2.6-2.7, forexample 2.7-2.8, such as 2.8-2.9, for example 2.9-3.0, such as 3.0-3.5,for example 3.5-4.0, such as 4.0-4.5, for example 4.5-5.0, such as5.0-6.0, for example 6.0-7.0, such as 7.0-8.0, for example 8.0-9.0, suchas 9.0-10.0 mm.

In another embodiment of the invention, the distance between the surfaceof the matrix material and the print head or nozzle(s) is in the range0.01-10.0 mm, such as 0.02-10.0, for example 0.03-10.0, such as0.04-10.0, for example 0.05-10.0, such as 0.06-10.0, for example0.07-10.0, such as 0.08-10.0, for example 0.1-10.0, such as 0.2-10.0,for example 0.3-10.0, such as 0.4-10.0, for example 0.5-10.0, such as0.6-10.0, for example 0.7-10.0, such as 0.8-10.0, for example 0.9-10.0,such as 1.0-10.0, for example 1.1-10.0, such as 1.2-10.0, for example1.3-10.0, such as 1.4-10.0, for example 1.5-10.0, such as 1.6-10.0, forexample 1.7-10.0, such as 1.8-10.0, for example 1.9-10.0, such as2.0-10.0, for example 2.1-10.0, such as 2.2-10.0, for example 2.3-10.0,such as 2.4-10.0, for example 2.5-10.0, such as 2.6-10.0, for example2.7-10.0, such as 2.8-10.0, for example 2.9-10.0, such as 3.0-10.0, forexample 3.5-10.0, such as 4.0-10.0, for example 4.5-10.0, such as5.0-10.0, for example 6.0-10.0, such as 7.0-10.0, for example 8.0-10.0,such as 9.0-10.0 mm.

In another embodiment of the invention, the distance between the surfaceof the matrix material and the print head or nozzle(s) is in the range0.01-0.02 mm, such as 0.01-0.03, for example 0.01-0.04, such as0.01-0.05, for example 0.01-0.06, such as 0.01-0.07, for example0.01-0.08, such as 0.01-0.09, for example 0.01-0.2, such as 0.01-0.3,for example 0.01-0.4, such as 0.01-0.5, for example 0.01-0.6, such as0.01-0.7, for example 0.01-0.8, such as 0.01-0.9, for example 0.01-1.0,such as 0.01-1.1, for example 0.01-1.2, such as 0.01-1.3, for example0.01-1.4, such as 0.01-1.5, for example 0.01-1.6, such as 0.01-1.7, forexample 0.01-1.8, such as 0.01-1.9, for example 0.01-2.0, such as0.01-2.1, for example 0.01-2.2, such as 0.01-2.3, for example 0.01-2.4,such as 0.01-2.5, for example 0.01-2.6, such as 0.01-2.7, for example0.01-2.8, such as 0.01-2.9, for example 0.01-3.0, such as 0.01-3.5, forexample 0.01-4.0, such as 0.01-4.5, for example 0.01-5.0, such as0.01-6.0, for example 0.01-7.0, such as 0.01-8.0, for example 0.01-9.0,such as 0.01-10.0 mm.

In one embodiment, each droplet of the printed fluid or liquidcomposition traverses a distance from nozzle the to surface of asubstrate or matrix material that varies between each droplet within arange of 0.01% to a maximum of 10%; such as 0.01 to 0.1%, for example0.1 to 1%, such as 1 to 2%, for example 2 to 3%, such as 3 to 4%, forexample 4 to 5%, such as 5 to 6%, for example 6 to 7%, such as 7 to 8%,for example 8 to 9%, such as 9 to 10%.

In one embodiment, each droplet of the printed fluid or liquidcomposition traverses a distance from nozzle the to surface of asubstrate or matrix material with a velocity that varies between eachdroplet within a range of 0.01% to a maximum of 10%; such as 0.01 to0.1%, for example 0.1 to 1%, such as 1 to 2%, for example 2 to 3%, suchas 3 to 4%, for example 4 to 5%, such as 5 to 6%, for example 6 to 7%,such as 7 to 8%, for example 8 to 9%, such as 9 to 10%.

The perpendicular mode of deposition of droplets and the shorterdistance between nozzle and surface of the matrix material makesprinting more efficient than spraying. With printing, one may print allthe way to the edge of the surface of the matrix material, whereas aspraying technique will deposit a composition in an angled way, thereby‘over-spraying’ to reach the edges of the surface. This has to do withboth the angled spraying, the generation of aerosols and the greaterdistance from nozzle to surface when spraying. The angled deposition ofa fluid or liquid composition with spraying causes the distance for eachdroplet to vary greatly. Thus, the composition will be deposited athigher density in the middle of the spray and a lower density at theedge of the spray, resulting in a less uniform distribution andpromoting a concentration gradient. Thus, printing may occur essentiallywithout generating aerosols.

Differences between spraying and printing are illustrated in FIGS. 1Aand 1B.

The material of the composition to be deposited on the surface of amatrix material is deposited in a discrete manner, that is, in discretelocations or positions on the surface of the matrix material.

In one embodiment, the invention relates to a device comprising a matrixmaterial, comprising discretely deposited material. The discretelydeposited material may be denoted ‘islands’. These islands thus comprisediscrete positions on the surface of the matrix material of the device.The islands may comprise a pharmaceutical composition.

Droplet Size of the Fluid or Liquid Composition

When printing a fluid or liquid composition onto a surface of a matrixmaterial, the amount of liquid deposited per position on the matrixsurface; i.e. the volume of each droplet, is in the pico liter (pL) tonano liter (nL) range. In one embodiment, the amount of liquid depositedper position on the matrix surface; i.e. the volume of each droplet isless than 100 nL, such as less than 90 nL, for example less than 80 nL,such as less than 70 nL, for example less than 60 nL, such as less than50 nL, for example less than 40 nL, such as less than 30 nL, for exampleless than 20 nL, such as less than 10 nL, for example less than 1 nL or1000 pL, such as less than 900 pL, for example less than 800 pL, such asless than 700 pL, for example less than 600 pL, such as less than 500pL, for example less than 400 pL, such as less than 300 pL, for exampleless than 250 pL, such as less than 200 pL, for example less than 150pL, such as less than 100 pL, for example less than 90 pL, such as lessthan 80 pL, for example less than 70 pL, such as less than 60 pL, forexample less than 50 pL, such as less than 40 pL, for example less than30 pL, such as less than 20 pL, for example less than 10 pL, such asless than 9 pL, for example less than 8 pL, such as less than 7 pL, forexample less than 6 pL, such as less than 5 pL, for example less than 4pL, such as less than 3 pL, for example less than 2 pL, such as lessthan 1 pL per position.

In another embodiment, the amount of liquid deposited per position onthe surface of the matrix; i.e. the volume of each droplet, is in therange of 0.1 pL to 100 nL; such as 0.1-1 pL, for example 1-5 pL, such as5-10 pL, for example 10-20 pL, such as 20-30 pL, for example 30-40 pL,such as 40-50 pL, for example 50-60 pL, such as 60-70 pL, for example70-80 pL, such as 80-90 pL, for example 90-100 pL, such as 100-110 pL,for example 110-120 pL, such as 120-130 pL, for example 130-140 pL, suchas 140-150 pL, for example 150-160 pL, such as 160-170 pL, for example170-180 pL, such as 180-190 pL, for example 190-200 pL, such as 200-250pL, for example 250-300 pL, such as 300-350 pL, for example 350-400 pL,such as 400-450 pL, for example 450-500 pL, such as 500-550 pL, forexample 550-600 pL, such as 600-650 pL, for example 650-700 pL, such as700-750 pL, for example 750-800 pL, such as 800-850 pL, for example850-900 pL, such as 900-950 pL, for example 950-1000 pL or 1 nL, such as1-2 nL, for example 2-3 nL, such as 3-4 nL, for example 4-5 nL, such as5-6 nL, for example 6-7 nL, such as 7-8 nL, for example 8-9 nL, such as9-10 nL, for example 10-15 nL, such as 15-20 nL, for example 20-25 nL,such as 25-30 nL, for example 30-35 nL, such as 35-40 nL, for example40-45 nL, such as 45-50 nL, for example 50-60 nL, such as 60-70 nL, forexample 70-80 nL, such as 80-90 nL, for example 90-100 nL.

In another embodiment, the amount of liquid deposited per position onthe surface of the matrix; i.e. the volume of each droplet, is in therange of 0.1 pL-100 nL, for example 1 pL-100 nL, such as 5 pL-100 nL,for example 10 pL-100 nL, such as 20 pL-100 nL, for example 30 pL-100nL, such as 40 pL-100 nL, for example 50 pL-100 nL, such as 60 pL-100nL, for example 70 pL-100 nL, such as 80 pL-100 nL, for example 90pL-100 nL, such as 100 pL-100 nL, for example 110 pL-100 nL, such as 120pL-100 nL, for example 130 pL-100 nL, such as 140 pL-100 nL, for example150 pL-100 nL, such as 160 pL-100 nL, for example 170 pL-100 nL, such as180 pL-100 nL, for example 190 pL-100 nL, such as 200 pL-100 nL, forexample 250 pL-100 nL, such as 300 pL-100 nL, for example 350 pL-100 nL,such as 400 pL-100 nL, for example 450 pL-100 nL, such as 500 pL-100 nL,for example 550 pL-100 nL, such as 600 pL-100 nL, for example 650 pL-100nL, such as 700 pL-100 nL, for example 750 pL-100 nL, such as 800 pL-100nL, for example 850 pL-100 nL, such as 900 pL-100 nL, for example 950pL-100 nL, such as 1-100 nL, for example 2-100 nL, such as 3-100 nL, forexample 4-100 nL, such as 5-100 nL, for example 6-100 nL, such as 7-100nL, for example 8-100 nL, such as 9-100 nL, for example 10-100 nL, suchas 15-100 nL, for example 20-100 nL, such as 25-100 nL, for example30-100 nL, such as 35-100 nL, for example 40-100 nL, such as 45-100 nL,for example 50-100 nL, such as 60-100 nL, for example 70-100 nL, such as80-100 nL, for example 90-100 nL.

In yet another embodiment, the amount of liquid deposited per positionon the surface of the matrix; i.e. the volume of each droplet, is in therange of 0.1-1 pL, for example 0.1-5 pL, such as 0.1-10 pL, for example0.1-20 pL, such as 0.1-30 pL, for example 0.1-40 pL, such as 0.1-50 pL,for example 0.1-60 pL, such as 0.1-70 pL, for example 0.1-80 pL, such as0.1-90 pL, for example 0.1-100 pL, such as 0.1-110 pL, for example0.1-120 pL, such as 0.1-130 pL, for example 0.1-140 pL, such as 0.1-150pL, for example 0.1-160 pL, such as 0.1-170 pL, for example 0.1-180 pL,such as 0.1-190 pL, for example 0.1-200 pL, such as 0.1-250 pL, forexample 0.1-300 pL, such as 0.1-350 pL, for example 0.1-400 pL, such as0.1-450 pL, for example 0.1-500 pL, such as 0.1-550 pL, for example0.1-600 pL, such as 0.1-650 pL, for example 0.1-700 pL, such as 0.1-750pL, for example 0.1-800 pL, such as 0.1-850 pL, for example 0.1-900 pL,such as 0.1-950 pL, for example 0.1-1000 pL or 1 nL, such as 0.1 pL-2nL, for example 0.1 pL-3 nL, such as 0.1 pL-4 nL, for example 0.1 pL-5nL, such as 0.1 pL-6 nL, for example 0.1 pL-7 nL, such as 0.1 pL-8 nL,for example 0.1 pL-9 nL, such as 0.1 pL-10 nL, for example 0.1 pL-15 nL,such as 0.1 pL-20 nL, for example 0.1 pL-25 nL, such as 0.1 pL-30 nL,for example 0.1 pL-35 nL, such as 0.1 pL-40 nL, for example 0.1 pL-45nL, such as 0.1 pL-50 nL, for example 0.1 pL-60 nL, such as 0.1 pL-70nL, for example 0.1 pL-80 nL, such as 0.1 pL-90 nL, for example 0.1pL-100 nL.

The droplet size for each droplet is preferably essentially identical,wherein the droplet size of any two droplets expelled from a printeraccording to the present invention may vary less that 10%, such as lessthan 8%, for example less than 6%, such as less than 4%, for exampleless than 2%, such as less than 1%. The droplet size of any two dropletsexpelled from a printer according to the present invention may vary inthe range of 0.1-10%, such as 0.1-1%, for example 1-2%, such as 2-3%,for example 3-4%, such as 4-5%, for example 5-6%, such as 6-7%, forexample 7-8%, such as 8-9%, for example 9-10%.

The total volume of fluid or liquid composition to be deposited byprinting in the form of droplets in a preferred embodiment essentiallydoes not result in any swelling of the matrix material.

Distance Between Droplets Deposited onto a Surface by Printing

When printing a fluid or liquid composition onto a surface of a matrixmaterial, the droplets expelled from the nozzles of the print head arepreferably deposited onto said surface with a certain predetermineddistance between every two droplets.

In one embodiment, the distance between every two droplets deposited byprinting onto the matrix surface is less than 2 mm, such as less than1.9 mm, for example less than 1.8 mm, such as less than 1.7 mm, forexample less than 1.6 mm, such as less than 1.5 mm, for example lessthan 1.4 mm, such as less than 1.3 mm, for example less than 1.3 mm,such as less than 1.2 mm, for example less than 1.1 mm, such as lessthan 1.0 mm, for example less than 0.9 mm, such as less than 0.8 mm, forexample less than 0.7 mm, such as less than 0.6 mm, for example lessthan 0.5 mm, such as less than 0.4 mm, for example less than 0.3 mm,such as less than 0.2 mm, for example less than 0.1 mm, such as lessthan 0.09 mm, for example less than 0.08 mm, such as less than 0.07 mm,for example less than 0.06 mm, such as less than 0.05 mm, for exampleless than 0.04 mm, such as less than 0.03 mm, for example less than 0.02mm, such as less than 0.01 mm.

In another embodiment, the distance between every two droplets depositedby printing onto the matrix surface is in the range of 0.01 to 2 mm; forexample 0.01-0.02 mm, such as 0.02-0.03 mm, for example 0.03-0.04 mm,such as 0.04-0.05 mm, for example 0.05-0.06 mm, such as 0.06-0.07 mm,for example 0.07-0.08 mm, such as 0.08-0.09 mm, for example 0.09-0.1 mm,such as 0.1-0.2 mm, for example 0.2-0.3 mm, such as 0.3-0.4 mm, forexample 0.4-0.5 mm, such as 0.5-0.6 mm, for example 0.6-0.7 mm, such as0.7-0.8 mm, for example 0.8-0.9 mm, such as 0.9-1.0 mm, for example1.0-1.1 mm, such as 1.1-1.2 mm, for example 1.2-1.3 mm, such as 1.3-1.4mm, for example 1.4-1.5 mm, such as 1.5-1.6 mm, for example 1.6-1.7 mm,such as 1.7-1.8 mm, for example 1.8-1.9 mm, such as 1.9-2.0 mm.

In another embodiment, the distance between every two droplets depositedby printing onto the matrix surface is in the range of 0.01-2.0 mm, suchas 0.02-2.0 mm, for example 0.03-2.0 mm, such as 0.04-2.0 mm, forexample 0.05-2.0 mm, such as 0.06-2.0 mm, for example 0.07-2.0 mm, suchas 0.08-2.0 mm, for example 0.09-2.0 mm, such as 0.1-2.0 mm, for example0.2-2.0 mm, such as 0.3-2.0 mm, for example 0.4-2.0 mm, such as 0.5-2.0mm, for example 0.6-2.0 mm, such as 0.7-2.0 mm, for example 0.8-2.0 mm,such as 0.9-2.0 mm, for example 1.0-2.0 mm, such as 1.1-2.0 mm, forexample 1.2-2.0 mm, such as 1.3-2.0 mm, for example 1.4-2.0 mm, such as1.5-2.0 mm, for example 1.6-2.0 mm, such as 1.7-2.0 mm, for example1.8-2.0 mm, such as 1.9-2.0 mm.

In yet another embodiment, the distance between every two dropletsdeposited by printing onto the matrix surface is in the range of0.01-0.02 mm, such as 0.01-0.03 mm, for example 0.01-0.04 mm, such as0.01-0.05 mm, for example 0.01-0.06 mm, such as 0.01-0.07 mm, forexample 0.01-0.08 mm, such as 0.01-0.09 mm, for example 0.01-0.1 mm,such as 0.01-0.2 mm, for example 0.01-0.3 mm, such as 0.01-0.4 mm, forexample 0.01-0.5 mm, such as 0.01-0.6 mm, for example 0.01-0.7 mm, suchas 0.01-0.8 mm, for example 0.01-0.9 mm, such as 0.01-1.0 mm, forexample 0.01-1.1 mm, such as 0.01-1.2 mm, for example 0.01-1.3 mm, suchas 0.01-1.4 mm, for example 0.01-1.5 mm, such as 0.01-1.6 mm, forexample 0.01-1.7 mm, such as 0.01-1.8 mm, for example 0.01-1.9 mm, suchas 0.01-2.0 mm.

The distance between every two droplets deposited by printing onto thematrix surface is preferably essentially identical, wherein the distancemay vary less that 10%, such as less than 8%, for example less than 6%,such as less than 4%, for example less than 2%, such as less than 1%.The droplet size of any two droplets expelled from a printer accordingto the present invention may vary in the range of 0.1-10%, such as0.1-1%, for example 1-2%, such as 2-3%, for example 3-4%, such as 4-5%,for example 5-6%, such as 6-7%, for example 7-8%, such as 8-9%, forexample 9-10%.

Droplet Evaporation

When tiny droplets of a fluid pharmaceutical composition comprising oneor more bioactive agents is printed onto the surface of a matrix or adevice, a subsequent drying step, including a lyophilisation step, ofthe matrix or device is not required; the reason being that the tinydroplets printed in discrete positions on the surface of the matrix orthe device will readily evaporate. This has the further advantage ofavoiding any undesirable swelling of the matrix material—a swellingwhich accompanies most if not all state-of-the-art sprayingtechnologies.

Thus, in one embodiment, the fluid droplets comprising one or morebioactive agents which are printed onto the surface of a matrix or thesurface of a device according to the present invention will not exceed asize that allows the droplets to evaporate within maximum 30 seconds,such as less than 25 seconds, for example less than 20 seconds, such asless than 15 seconds, for example less than 10 seconds, such as lessthan 5 seconds, for example less than 1 second after being printed ontothe surface of the matrix or the surface of the device.

In one embodiment, the fluid droplets comprising one or more bioactiveagents which are printed onto the surface of a matrix or the surface ofa device according to the present invention will not exceed a size thatallows the droplets to evaporate within 0.1-1 second, such as 1-2, forexample 2-3, such as 3-4, for example 4-5, such as 5-6, for example 6-7,such as 7-8, for example 8-9, such as 9-10, for example 11-12, such as12-13, for example 13-14, such as 14-15, for example 15-16, such as16-17, for example 17-18, such as 18-19, for example 19-20, such as20-25, for example 25-30 seconds after being printed onto the surface ofthe matrix or the surface of the device.

The above-cited time for evaporation can be achieved by controllingdroplet size, temperature of the droplet and temperature of the surfaceof the matrix or the device onto which the droplet is printed. Further,modifying the surface properties of the underlying matrix material(hydrophobicity, chemical heterogeneity, roughness) may alterevaporation time.

The evaporation of the fluid droplets on the surface of a substrate canin principle be aided in various ways. In principle the droplets canevaporate on the surface without dissolution of the surface, or thefluid can be a solvent for the surface and thus be absorbed in thesurface, thereby effectively aiding in the evaporation process.

It is preferred that the droplets evaporate without dissolving orinteracting with the surface of the matrix material or the devicecomprising said matrix material. Thus, as a consequence of the rapidevaporation of the fluid part of the droplet printed onto the surface ofthe matrix, the matrix is printed with the pharmaceutical compositionforming part of the droplet essentially without swelling and/oressentially without resulting in any other physical change of thesurface structure of the matrix material or device.

When a droplet evaporates on the surface of a matrix material or devicewithout dissolution of the surface material, different evaporation modescan be observed. A droplet can evaporate with the contact angle beingessentially constant while the contact radius decreases (constant anglemode). Alternatively, the contact radius can remain essentially constantwhile the contact angle decreases, in which case the droplet becomesmore flat over time (constant radius mode or pinning). Alternativelyboth of the above-mentioned modes can occur, in which case both thecontact angle and the contact radius will change during evaporation(non-constant mode).

Usually, droplets evaporate in different modes. Thus, the use of tiny,uniformly sized droplets that evaporates rapidly upon contacting thesurface of a matrix material or a device will add to the uniformity ofprinting of the compositions onto the surface of the matrix material orthe device.

Operating Temperature

The temperature of the fluid or liquid composition, or the temperatureof the environment wherein the fluid or liquid composition is to beprinted, is in one embodiment the ambient temperature. In anotherembodiment, the temperature is in the range from sub-zero degreescelcius to 150 degrees celcius; such as −100° C. to −50° C., for example−50° C. to 0° C., such as 0-10° C., for example 10-20° C., such as20-30° C., for example 30-40° C., such as 40-50° C., for example 50-60°C., such as 60-70° C., for example 70-80° C., such as 80-90° C., forexample 90-100° C., such as 100-125° C., for example 125-150° C.

Deposition of One or More Pharmaceutical Compositions by Other Methodsthan Printing

The present invention in one embodiment relates to a medical devicecomprising a composition, such as a pharmaceutical composition, which isdeposited onto a matrix material e.g. onto the surface of the matrixmaterial, wherein said matrix material comprising a pharmaceuticalcomposition is comprised in a container according to the presentinvention. The deposition of the composition onto the matrix may in oneembodiment be performed by any method know in the art such as byprinting, spraying, soaking, dipping, coating, saturating, pressuring,sprinkling, pouring, spreading, greasing, smearing, dabbing, rubbing orpainting the pharmaceutical composition onto a premade matrix or bydipping of a premade matrix into the pharmaceutical composition.Alternatively, the pharmaceutical composition can be deposited into oronto the matrix during preparation of said matrix e.g. by mixing it intoone or more of the matrix material components.

Bioactive Agents of the Pharmaceutical Composition

In a preferred embodiment, the invention relates to a pharmaceuticalcomposition initially in fluid or liquid form, comprising one or morebioactive agents, optionally in combination with further active agentsor substances, thus comprising a pharmaceutical composition thatincludes a pharmaceutically acceptable carrier and one or more bioactiveagents, such as thrombin or thrombin in combination with fibrinogen, orthrombin and fibrinogen in combination with Factor XIII, or thrombin andfibrinogen and Factor XIII in combination with tranexamic acid.

The pharmaceutical composition is in one embodiment printed onto asurface of the matrix of the device, thereby depositing the agents ofthe composition onto the surface of the matrix in a controlled manner.One or more of said compositions may be printed each at one or morediscrete positions on the surface of the matrix material.

Non-limiting examples of useful biologically active agents which can bepresent alone or in combination with the above-cited bioactive agentsselected from the group of thrombin or thrombin in combination withfibrinogen, or thrombin and fibrinogen in combination with Factor XIII,or thrombin and fibrinogen and Factor XIII in combination withtranexamic acid, include the following expanded therapeutic categories:hemostatic and anti-fibrinolytic agents, wound healing or promotingagents, adhesives and surfactants anabolic agents, antacids,anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents,anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics,anti-infective agents, anti-inflammatory agents, anti-manic agents,anti-nauseants, anti-neoplastic agents, anti-obesity agents,anti-pyretic and analgesic agents, anti-spasmodic agents,anti-thrombotic agents, anti-uricemic agents, anti-anginal agents,anti-histamines, anti-tussives, appetite suppressants, biologicals,cerebral dilators, coronary dilators, decongestants, diuretics,diagnostic agents, erythropoietic agents, expectorants, gastrointestinalsedatives hyperglycemic agents, hypnotics, hypoglycemic agents, ionexchange resins, laxatives, mineral supplements, mucolytic agents,neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives,stimulants, thyroid and anti-thyroid agents, uterine relaxants,vitamins, antigenic materials, analgetics and prodrugs.

Specific examples of useful biologically active substances from theabove categories include: (a) anti-neoplastics such as androgeninhibitors, anti-metabolites, cytotoxic agents, immunomodulators; (b)anti-tussives such as dextromethorphan, dextromethorphan hydrobromide,noscapine, carbetapentane citrate, and chlophedianol hydrochloride; (c)antihistamines such aschlorpheniramine maleat, phenindamine tartrate,zyrilamine mafeate, doxylamine succinate, and phenyltcloxamine citrate;(d) decongestants such as phenylephrine hydrochloride,chenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, andephedrine; (e) various alkaloid such as codeine phosphate, codeinesulfate and morphine-(mineral supplements such as potassium chloride,zinc chloride, calcium carbonates, magnesium oxide, and other alkalimetal and alkaline earth metal salts; (g) ion exchange resins such ascholestryramine; (h) anti-arrhythmics such as N-acetylprocainamide; (i)antipyretics and analgesics such as acetaminophen, aspirin andibuprofen; (j) appetite suppressants such as phenyl-propanolaminehydrochloride or caffeine; (k) expectorants such as guaifenesin; (l)antacids such as aluminum hydroxide and magnesium hydroxide; (m)biologicals such as peptides, polypeptides, proteins and amino acids,hormones, interferons or cytokines and other bioactive peptidiccompounds, such as hGH, tPA, calcitonin, ANF, EPO and insulin; (n)anti-infective agents such as anti-fungals, RTI anti-virals, antisepticsand antibiotics; and (o) antigenic materials, particularly those usefulin vaccine applications.

Pharmaceutically acceptable carriers may be prepared from a wide rangeof materials. Without being limited thereto, such materials includediluents, binders and adhesives, lubricants, disintegrants, colorants,bulking agents (an additive that increases the bulk of a substance),flavorings, sweeteners, and miscellaneous materials such as buffers andabsorbents in order to prepare a particular medicated suppository.

Concentration of the Bioactive Agent of the Fluid or Liquid Composition

Bioactive agents of the fluid or liquid composition according to thepresent invention may be used in any suitable concentration, i.e. apharmaceutical relevant concentration for achieving a biological effect.

In one embodiment, the bioactive agent is an enzyme, said enzyme beingpresent in the fluid or liquid composition at a concentration of lessthan 1,000,000 IU/ml, such as less than 950,000 IU/ml, for example lessthan 900,000 IU/ml, such as less than 850,000 IU/ml, for example lessthan 800,000 IU/ml, such as less than 750,000 IU/ml, for example lessthan 700,000 IU/ml, such as less than 650,000 IU/ml, for example lessthan 600,000 IU/ml, such as less than 550,000 IU/ml, for example lessthan 500,000 IU/ml, such as less than 450,000 IU/ml, for example lessthan 400,000 IU/ml, such as less than 350,000 IU/ml, for example lessthan 300,000 IU/ml, such as less than 250,000 IU/ml, for example lessthan 200,000 IU/ml, such as less than 150,000 IU/ml, for example lessthan 100,000 IU/ml, such as less than 95,000 IU/ml, for example lessthan 90,000 IU/ml, such as less than 85,000 IU/ml, for example less than80,000 IU/ml, such as less than 75,000 IU/ml, for example less than70,000 IU/ml, such as less than 65,000 IU/ml, for example less than60,000 IU/ml, such as less than 55,000 IU/ml, for example less than50,000 IU/ml, such as less than 45,000 IU/ml, for example less than40,000 IU/ml, such as less than 35,000 IU/ml, for example less than30,000 IU/ml, such as less than 25,000 IU/ml, for example less than20,000 IU/ml, such as less than 15,000 IU/ml, for example less than10,000 IU/ml, such as less than 9,500 IU/ml, for example less than 9,000IU/ml, such as less than 8,500 IU/ml, for example less than 8,000 IU/ml,such as less than 7,500 IU/ml, for example less than 7,000 IU/ml, suchas less than 6,500 IU/ml, for example less than 6,000 IU/ml, such asless than 5,500 IU/ml, for example less than 5,000 IU/ml, such as lessthan 4,500 IU/ml, for example less than 4,000 IU/ml, such as less than3,500 IU/ml, for example less than 3,000 IU/ml, such as less than 2,500IU/ml, for example less than 2,000 IU/ml, such as less than 1,500 IU/ml,for example less than 1,000 IU/ml, such as less than 750 IU/ml, forexample less than 500 IU/ml, such as less than 450 IU/ml, for exampleless than 400 IU/ml, such as less than 350 IU/ml, for example less than300 IU/ml, such as less than 250 IU/ml, for example less than 200 IU/ml,such as less than 150 IU/ml, for example less than 100 IU/ml, such asless than 50 IU/ml, for example less than 10 IU/ml, such as less than 1IU/ml.

In one embodiment, the bioactive agent is an enzyme, said enzyme beingpresent in the fluid or liquid composition at a concentration in therange of 1 IU/ml to 1,000,000 IU/ml; such as 1-10 IU/ml, for example10-50 IU/ml, such as 50-100 IU/ml, for example 100-150 IU/ml, such as150-200 IU/ml, for example 200-250 IU/ml, such as 250-300 IU/ml, forexample 300-350 IU/ml, such as 350-400 IU/ml, for example 400-450 IU/ml,such as 450-500 IU/ml, for example 500-750 IU/ml, such as 750-1000IU/ml, for example 1000-1500 IU/ml, such as 1500-2000 IU/ml, for example2000-2500 IU/ml, such as 2500-3000 IU/ml, for example 3000-3500 IU/ml,such as 3500-4000 IU/ml, for example 4000-4500 IU/ml, such as 4500-5000IU/ml, for example 5000-5500 IU/ml, such as 5500-6000 IU/ml, for example6000-6500 IU/ml, such as 6500-7000 IU/ml, for example 7000-7500 IU/ml,such as 7500-8000 IU/ml, for example 8000-8500 IU/ml, such as 8500-9000IU/ml, for example 9000-9500 IU/ml, such as 9500-10,000 IU/ml, forexample 10,000-11,000 IU/ml, such as 11,000-12,000 IU/ml, for example12,000-13,000 IU/ml, such as 13,000-14,000 IU/ml, for example14,000-15,000 IU/ml, such as 15,000-16,000 IU/ml, for example16,000-17,000 IU/ml, such as 17,000-18,000 IU/ml, for example18,000-19,000 IU/ml, such as 19,000-20,000 IU/ml, for example20,000-25,000 IU/ml, such as 25,000-30,000 IU/ml, for example30,000-35,000 IU/ml, such as 35,000-40,000 IU/ml, for example40,000-45,000 IU/ml, such as 45,000-50,000 IU/ml, for example50,000-55,000 IU/ml, such as 55,000-60,000 IU/ml, for example60,000-65,000 IU/ml, such as 65,000-70,000 IU/ml, for example70,000-75,000 IU/ml, such as 75,000-80,000 IU/ml, for example80,000-85,000 IU/ml, such as 85,000-90,000 IU/ml, for example90,000-95,000 IU/ml, such as 95,000-100,000 IU/ml, for example100,000-150,000 IU/ml, such as 150,000-200,000 IU/ml, for example200,000-250,000 IU/ml, such as 250,000-300,000 IU/ml, for example300,000-350,000 IU/ml, such as 350,000-400,000 IU/ml, for example400,000-450,000 IU/ml, such as 450,000-500,000 IU/ml, for example500,000-550,000 IU/ml, such as 550,000-600,000 IU/ml, for example600,000-650,000 IU/ml, such as 650,000-700,000 IU/ml, for example700,000-750,000 IU/ml, such as 750,000-800,000 IU/ml, for example800,000-850,000 IU/ml, such as 850,000-900,000 IU/ml, for example900,000-950,000 IU/ml, such as 950,000-1,000,000 IU/ml.

In another embodiment, the bioactive agent is an enzyme, said enzymebeing present in the fluid or liquid composition at a concentration inthe range of 1-1,000,000 IU/ml, for example 10-1,000,000 IU/ml, such as50-1,000,000 IU/ml, for example 100-1,000,000 IU/ml, such as150-1,000,000 IU/ml, for example 200-1,000,000 IU/ml, such as250-1,000,000 IU/ml, for example 300-1,000,000 IU/ml, such as350-1,000,000 IU/ml, for example 400-1,000,000 IU/ml, such as450-1,000,000 IU/ml, for example 500-1,000,000 IU/ml, such as750-1,000,000 IU/ml, for example 1000-1,000,000 IU/ml, such as1500-1,000,000 IU/ml, for example 2000-1,000,000 IU/ml, such as2500-1,000,000 TU/ml, for example 3000-1,000,000 IU/ml, such as3500-1,000,000 IU/ml, for example 4000-1,000,000 IU/ml, such as4500-1,000,000 IU/ml, for example 5000-1,000,000 IU/ml, such as5500-1,000,000 IU/ml, for example 6000-1,000,000 IU/ml, such as6500-1,000,000 IU/ml, for example 7000-1,000,000 IU/ml, such as7500-1,000,000 IU/ml, for example 8000-1,000,000 IU/ml, such as8500-1,000,000 IU/ml, for example 9000-1,000,000 IU/ml, such as9500-1,000,000 IU/ml, for example 10,000-1,000,000 IU/ml, such as11,000-1,000,000 IU/ml, for example 12,000-1,000,000 IU/ml, such as13,000-1,000,000 IU/ml, for example 14,000-1,000,000 IU/ml, such as15,000-1,000,000 IU/ml, for example 16,000-1,000,000 IU/ml, such as17,000-1,000,000 IU/ml, for example 18,000-1,000,000 IU/ml, such as19,000-1,000,000 IU/ml, for example 20,000-1,000,000 IU/ml, such as25,000-1,000,000 IU/ml, for example 30,000-1,000,000 IU/ml, such as35,000-1,000,000 IU/ml, for example 40,000-1,000,000 IU/ml, such as45,000-1,000,000 IU/ml, for example 50,000-1,000,000 IU/ml, such as55,000-1,000,000 IU/ml, for example 60,000-1,000,000 IU/ml, such as65,000-1,000,000 IU/ml, for example 70,000-1,000,000 IU/ml, such as75,000-1,000,000 IU/ml, for example 80,000-1,000,000 IU/ml, such as85,000-1,000,000 IU/ml, for example 90,000-1,000,000 IU/ml, such as95,000-1,000,000 IU/ml, for example 100,000-1,000,000 IU/ml, such as150,000-1,000,000 IU/ml, for example 200,000-1,000,000 IU/ml, such as250,000-1,000,000 IU/ml, for example 300,000-1,000,000 IU/ml, such as350,000-1,000,000 IU/ml, for example 400,000-1,000,000 IU/ml, such as450,000-1,000,000 IU/ml, for example 500,000-1,000,000 IU/ml, such as550,000-1,000,000 IU/ml, for example 600,000-1,000,000 IU/ml, such as650,000-1,000,000 IU/ml, for example 700,000-1,000,000 IU/ml, such as750,000-1,000,000 IU/ml, for example 800,000-1,000,000 IU/ml, such as850,000-1,000,000 IU/ml, for example 900,000-1,000,000 IU/ml, such as950,000-1,000,000 IU/ml.

In yet another embodiment, the bioactive agent is an enzyme, said enzymebeing present in the fluid or liquid composition at a concentration inthe range of such as 1-10 IU/ml, for example 1-50 IU/ml, such as 1-100IU/ml, for example 1-150 IU/ml, such as 1-200 IU/ml, for example 1-250IU/ml, such as 1-300 IU/ml, for example 1-350 IU/ml, such as 1-400IU/ml, for example 1-450 IU/ml, such as 1-500 IU/ml, for example 1-750IU/ml, such as 1-1000 IU/ml, for example 1-1500 IU/ml, such as 1-2000IU/ml, for example 1-2500 IU/ml, such as 1-3000 IU/ml, for example1-3500 IU/ml, such as 1-4000 IU/ml, for example 1-4500 IU/ml, such as1-5000 IU/ml, for example 1-5500 IU/ml, such as 1-6000 IU/ml, forexample 1-6500 IU/ml, such as 1-7000 IU/ml, for example 1-7500 IU/ml,such as 1-8000 IU/ml, for example 1-8500 IU/ml, such as 1-9000 IU/ml,for example 1-9500 IU/ml, such as 1-10,000 IU/ml, for example 1-11,000IU/ml, such as 1-12,000 IU/ml, for example 1-13,000 IU/ml, such as1-14,000 IU/ml, for example 1-15,000 IU/ml, such as 1-16,000 IU/ml, forexample 1-17,000 IU/ml, such as 1-18,000 IU/ml, for example 1-19,000IU/ml, such as 1-20,000 IU/ml, for example 1-25,000 IU/ml, such as1-30,000 IU/ml, for example 1-35,000 IU/ml, such as 1-40,000 IU/ml, forexample 1-45,000 IU/ml, such as 1-50,000 IU/ml, for example 1-55,000IU/ml, such as 1-60,000 IU/ml, for example 1-65,000 IU/ml, such as1-70,000 IU/ml, for example 1-75,000 IU/ml, such as 1-80,000 IU/ml, forexample 1-85,000 IU/ml, such as 1-90,000 IU/ml, for example 1-95,000IU/ml, such as 1-100,000 IU/ml, for example 1-150,000 IU/ml, such as1-200,000 IU/ml, for example 1-250,000 IU/ml, such as 1-300,000 IU/ml,for example 1-350,000 IU/ml, such as 1-400,000 IU/ml, for example1-450,000 IU/ml, such as 1-500,000 IU/ml, for example 1-550,000 IU/ml,such as 1-600,000 IU/ml, for example 1-650,000 IU/ml, such as 1-700,000IU/ml, for example 1-750,000 IU/ml, such as 1-800,000 IU/ml, for example1-850,000 IU/ml, such as 1-900,000 IU/ml, for example 1-950,000 IU/ml,such as 1-1,000,000 IU/ml.

In one embodiment, the bioactive agent is present in the fluid or liquidcomposition at a concentration of less than 1,000,000 mg/ml, such asless than 900,000 mg/ml, for example less than 800,000 mg/ml, such asless than 700,000 mg/ml, for example less than 600,000 mg/ml, such asless than 500,000 mg/ml, for example less than 400,000 mg/ml, such asless than 300,000 mg/ml, for example less than 200,000 mg/ml, such asless than 100,000 mg/ml, for example less than 90,000 mg/ml, such asless than 80,000 mg/ml, for example less than 70,000 mg/ml, such as lessthan 60,000 mg/ml, for example less than 50,000 mg/ml, such as less than40,000 mg/ml, for example less than 30,000 mg/ml, such as less than20,000 mg/ml, for example less than 10,000 mg/ml, such as less than 9000mg/ml, for example less than 8000 mg/ml, such as less than 7000 mg/ml,for example less than 6000 mg/ml, such as less than 5000 mg/ml, forexample less than 4000 mg/ml, such as less than 3000 mg/ml, for exampleless than 2000 mg/ml, such as less than 1000 mg/ml, for example lessthan 900 mg/ml, such as less than 800 mg/ml, for example less than 700mg/ml, such as less than 600 mg/ml, for example less than 500 mg/ml,such as less than 400 mg/ml, for example less than 300 mg/ml, such asless than 200 mg/ml, for example less than 100 mg/ml, such as less than10 mg/ml, for example less than 1 mg/ml, such as less than 1000 ug/ml,for example less than 900 ug/ml, such as less than 800 ug/ml, forexample less than 700 ug/ml, such as less than 600 ug/ml, for exampleless than 500 ug/ml, such as less than 400 ug/ml, for example less than300 ug/ml, such as less than 200 ug/ml, for example less than 100 ug/ml,such as less than 10 ug/ml, for example less than 1 ug/ml, such as lessthan 1000 ng/ml, for example less than 900 ng/ml, such as less than 800ng/ml, for example less than 700 ng/ml, such as less than 600 ng/ml, forexample less than 500 ng/ml, such as less than 400 ng/ml, for exampleless than 300 ng/ml, such as less than 200 ng/ml, for example less than100 ng/ml, such as less than 10 ng/ml, for example less than 1 ng/ml.

In one embodiment, the bioactive agent is present in the fluid or liquidcomposition at a concentration in the range of 1 ng/ml to 1,000,000mg/ml; such as 1-10 ng/ml, for example 10-100 ng/ml, such as 100-200ng/ml, for example 300-400 ng/ml, such as 400-500 ng/ml, for example500-600 ng/ml, such as 600-700 ng/ml, for example 700-800 ng/ml, such as800-900 ng/ml, for example 900-1000 ng/ml, such as 1-10 ug/ml, forexample 10-100 ug/ml, such as 100-200 ug/ml, for example 200-300 ug/ml,such as 300-400 ug/ml, for example 400-500 ug/ml, such as 500-600 ug/ml,for example 600-700 ug/ml, such as 700-800 ug/ml, for example 800-900ug/ml, such as 900-1000 ug/ml, for example 1-10 mg/ml, such as 10-100mg/ml, for example 100-200 mg/ml, such as 200-300 mg/ml, for example300-400 mg/ml, such as 400-500 mg/ml, for example 500-600 mg/ml, such as600-700 mg/ml, for example 700-800 mg/ml, such as 800-900 mg/ml, forexample 900-1000 mg/ml, such as 1000-2000 mg/ml, for example 2000-3000mg/ml, such as 3000-4000 mg/ml, for example 4000-5000 mg/ml, such as5000-6000 mg/ml, for example 6000-7000 mg/ml, such as 7000-8000 mg/ml,for example 8000-9000 mg/ml, such as 9000-10,000 mg/ml, for example10,000-20,000 mg/ml, such as 20,000-30,000 mg/ml, for example30,000-40,000 mg/ml, such as 40,000-50,000 mg/ml, for example50,000-60,000 mg/ml, such as 60,000-70,000 mg/ml, for example70,000-80,000 mg/ml, such as 80,000-90,000 mg/ml, for example90,000-100,000 mg/ml, such as 100,000-200,000 mg/ml, for example200,000-300,000 mg/ml, such as 300,000-400,000 mg/ml, for example400,000-500,000 mg/ml, such as 500,000-600,000 mg/ml, for example600,000-700,000 mg/ml, such as 700,000-800,000 mg/ml, for example800,000-900,000 mg/ml, such as 900,000-1,000,000 mg/ml.

In another embodiment, the bioactive agent is present in the fluid orliquid composition at a concentration in the range of 1 ng/ml-1,000,000mg/ml, for example 10 ng/ml-1,000,000 mg/ml, such as 100 ng/ml-1,000,000mg/ml, for example 300 ng/ml-1,000,000 mg/ml, such as 400ng/ml-1,000,000 mg/ml, for example 500 ng/ml-1,000,000 mg/ml, such as600 ng/ml-1,000,000 mg/ml, for example 700 ng/ml-1,000,000 mg/ml, suchas 800 ng/ml-1,000,000 mg/ml, for example 900 ng/ml-1,000,000 mg/ml,such as 1 ug/ml-1,000,000 mg/ml, for example 10 ug/ml-1,000,000 mg/ml,such as 100 ug/ml-1,000,000 mg/ml, for example 200 ug/ml-1,000,000mg/ml, such as 300 ug/ml-1,000,000 mg/ml, for example 400ug/ml-1,000,000 mg/ml, such as 500 ug/ml-1,000,000 mg/ml, for example600 ug/ml-1,000,000 mg/ml, such as 700 ug/ml-1,000,000 mg/ml, forexample 800 ug/ml-1,000,000 mg/ml, such as 900 ug/ml-1,000,000 mg/ml,for example 1-1,000,000 mg/ml, such as 10-1,000,000 mg/ml, for example100-1,000,000 mg/ml, such as 200-1,000,000 mg/ml, for example300-1,000,000 mg/ml, such as 400-1,000,000 mg/ml, for example500-1,000,000 mg/ml, such as 600-1,000,000 mg/ml, for example700-1,000,000 mg/ml, such as 800-1,000,000 mg/ml, for example900-1,000,000 mg/ml, such as 1000-1,000,000 mg/ml, for example2000-1,000,000 mg/ml, such as 3000-1,000,000 mg/ml, for example4000-1,000,000 mg/ml, such as 5000-1,000,000 mg/ml, for example6000-1,000,000 mg/ml, such as 7000-1,000,000 mg/ml, for example8000-1,000,000 mg/ml, such as 9000-1,000,000 mg/ml, for example10,000-1,000,000 mg/ml, such as 20,000-1,000,000 mg/ml, for example30,000-1,000,000 mg/ml, such as 40,000-1,000,000 mg/ml, for example50,000-1,000,000 mg/ml, such as 60,000-1,000,000 mg/ml, for example70,000-1,000,000 mg/ml, such as 80,000-1,000,000 mg/ml, for example90,000-1,000,000 mg/ml, such as 100,000-1,000,000 mg/ml, for example200,000-1,000,000 mg/ml, such as 300,000-1,000,000 mg/ml, for example400,000-1,000,000 mg/ml, such as 500,000-1,000,000 mg/ml, for example600,000-1,000,000 mg/ml, such as 700,000-1,000,000 mg/ml, for example800,000-1,000,000 mg/ml, such as 900,000-1,000,000 mg/ml.

In yet another embodiment, the bioactive agent is present in the fluidor liquid composition at a concentration in the range of 1-10 ng/ml, forexample 1-100 ng/ml, such as 1-200 ng/ml, for example 1-400 ng/ml, suchas 1-500 ng/ml, for example 1-600 ng/ml, such as 1-700 ng/ml, forexample 1-800 ng/ml, such as 1-900 ng/ml, for example 1-1000 ng/ml, suchas 1 ng/ml-10 ug/ml, for example 1 ng/ml-100 ug/ml, such as 1 ng/ml-200ug/ml, for example 1 ng/ml-300 ug/ml, such as 1 ng/ml-400 ug/ml, forexample 1 ng/ml-500 ug/ml, such as 1 ng/ml-600 ug/ml, for example 1ng/ml-700 ug/ml, such as 1 ng/ml-800 ug/ml, for example 1 ng/ml-900ug/ml, such as 1 ng/ml-1000 ug/ml, for example 1 ng/ml-10 mg/ml, such as1 ng/ml-100 mg/ml, for example 1 ng/ml-200 mg/ml, such as 1 ng/ml-300mg/ml, for example 1 ng/ml-400 mg/ml, such as 1 ng/ml-500 mg/ml, forexample 1 ng/ml-600 mg/ml, such as 1 ng/ml-700 mg/ml, for example 1ng/ml-800 mg/ml, such as 1 ng/ml-900 mg/ml, for example 1 ng/ml-1000mg/ml, such as 1 ng/ml-2000 mg/ml, for example 1 ng/ml-3000 mg/ml, suchas 1 ng/ml-4000 mg/ml, for example 1 ng/ml-5000 mg/ml, such as 1ng/ml-6000 mg/ml, for example 1 ng/ml-7000 mg/ml, such as 1 ng/ml-8000mg/ml, for example 1 ng/ml-9000 mg/ml, such as 1 ng/ml-10,000 mg/ml, forexample 1 ng/ml-20,000 mg/ml, such as 1 ng/ml-30,000 mg/ml, for example1 ng/ml-40,000 mg/ml, such as 1 ng/ml-50,000 mg/ml, for example 1ng/ml-60,000 mg/ml, such as 1 ng/ml-70,000 mg/ml, for example 1ng/ml-80,000 mg/ml, such as 1 ng/ml-90,000 mg/ml, for example 1ng/ml-100,000 mg/ml, such as 1 ng/ml-200,000 mg/ml, for example 1ng/ml-300,000 mg/ml, such as 1 ng/ml-400,000 mg/ml, for example 1ng/ml-500,000 mg/ml, such as 1 ng/ml-600,000 mg/ml, for example 1ng/ml-700,000 mg/ml, such as 1 ng/ml-800,000 mg/ml, for example 1ng/ml-900,000 mg/ml, such as 1 ng/ml-1,000,000 mg/ml.

The concentration of the bioactive agent in each droplet is preferablyessentially identical, wherein the concentration of any two dropletsexpelled from a printer according to the present invention may vary lessthat 10%, such as less than 8%, for example less than 6%, such as lessthan 4%, for example less than 2%, such as less than 1%. Theconcentration of any two droplets may vary in the range of 0.1-10%, suchas 0.1-1%, for example 1-2%, such as 2-3%, for example 3-4%, such as4-5%, for example 5-6%, such as 6-7%, for example 7-8%, such as 8-9%,for example 9-10%.

Uniform Distribution

When printing a fluid or liquid composition onto a matrix materialaccording to the present invention, the composition will be distributedin a uniform manner on the matrix material, i.e. there will beessentially no concentration gradient of the composition throughout thematrix material. This may be regarded as a uniform pattern arising fromthe uniform distribution. Further, deposition using the print technologyis also very precise, allowing the specific deposition onto discretelocations of the matrix material.

The uniform distribution arises from the use of a predetermined andessentially fixed ratio between droplet volume, distance between everytwo droplets and the concentration of the bioactive material of thedroplet. Achieving such a ratio is possible using the print technology,and permits the deposition of an essentially identical amount or volumeof fluid or liquid composition and/or bioactive agent per area unit ofthe matrix material. Achieving such a uniform distribution is notpossible to obtain from conventional techniques such as spraying.

Specific and numeric values for droplet volume or size, distance betweenevery two droplets and the droplet concentration of the bioactivematerial of the composition are given herein above. The predeterminedvalues for use in any embodiment to determine the ratio between dropletvolume, distance between every two droplets and the concentration of thedroplet may be chosen from any of the herein disclosed values.

A uniform distribution of a pharmaceutical composition initially influid or liquid form may be defined as a distribution wherein any twoarea units differ in volume of the printed composition or concentrationof bioactive agent by the most 10%, such as by the most 8%, for exampleby the most 6%, such as by the most 4%, for example by the most 2%, suchas by the most 1%. Any two area units has a uniform distribution thatmay vary in the range of 0.1-10%, such as 0.1-1%, for example 1-2%, suchas 2-3%, for example 3-4%, such as 4-5%, for example 5-6%, such as 6-7%,for example 7-8%, such as 8-9%, for example 9-10%.

A uniform distribution also arises from essentially all the fluid orliquid composition leaving the nozzle of the print head contacts thematrix material, whereby essentially no fluid or liquid composition iswasted in the process. The amount of fluid or liquid composition notcontacting the matrix material is less that 10%, such as less than 8%,for example less than 6%, such as less than 4%, for example less than2%, such as less than 1%.

Hemostatic and Anti-Fibrinolytic Agents

Hemostatic agents, or pro-coagulants or thrombotic agents, are agentsthat induce hemostasis. Thus, they shift the balance in favor of bloodcoagulation or clotting. Anti-fibrinolytic agents are also hemostaticagents, in that they prevent the degradation of the formed blood clot.

In a preferred embodiment, the device according to the present inventionis a hemostatic device. The hemostatic device may thus be imprinted withhemostatic agents.

The hemostatic device described herein may be used as a medicament.Accordingly, in a further aspect the present invention relates to amethod of promoting hemostasis in a patient in need thereof, said methodcomprising printing a pharmaceutical composition as defined herein ontoa device, and using the device to promote hemostasis.

Below are listed non-limiting examples of hemostatic agents that in oneembodiment may be included in the composition that is printed onto thedevice of the present invention.

Specific examples of hemostatic agents include coagulation factorsselected from the group consisting of prothrombin and/or thrombin,fibrinogen and/or fibrin, Factor V and/or Va, Factor VII and/or VIIa,Factor VIII and/or VIIIa, Factor IX and/or IXa, Factor X and/or Xa,Factor XI and/or XIa, Factor XII and/or XIIa, Factor XIII and/or XIIIa,and combinations thereof. Such compounds may be of any mammalian origin,such as of porcine or human origin, or may be obtained by recombinantmeans by methods well-known to the skilled person.

Coagulation factor concentrates are used to treat hemophilia, to reversethe effects of anticoagulants, and to treat bleeding in patients withimpaired coagulation factor synthesis or increased consumption.Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasmaare commonly-used coagulation factor products. Recombinant activatedhuman factor VII is are increasingly popular in the treatment of majorbleeding.

Fibronectin is excreted by fibroblasts in the proliferative pase ofwound healing. Fibrin and fibronectin cross-link together and form aplug that traps proteins and particles and prevents further blood loss.This fibrin-fibronectin plug is also the main structural support for thewound until collagen is deposited.

Additional agents that may be comprised in the composition to promotehemostasis include calcium ions to aid coagulation, and desmopressinwhich improve platelet function by activating arginine vasopressinreceptor 1A.

Anti-fibrinolytic agents may be selected from the group consisting oftranexamic acid, aminocaproic acid, aprotinin, pepstatin, leupeptin,antipain, chymostatin, gabexate, and mixtures thereof. In a preferredembodiment of the present invention, tranexamic acid comprises part ofthe composition, if any anti-fibrinolytic agent is comprised in thecomposition.

Further, the use of adsorbent chemicals, such as zeolites, and otherhemostatic agents is also being explored for use in sealing severeinjuries quickly.

QuikClot® brand hemostatic agent is manufactured by Z-MedicaCorporation. The original QuikClot® is a granular product that can bepoured directly on wounds to stop bleeding. It stops bleeding byadsorbing water from the blood thereby concentrating the clottingfactors, activating platelets and promoting steps in the coagulationcascade. It is composed of zeolite, a molecular sieve that trapsmolecules in a molecular “cage” and holding the trapped species byforming hydrogen bonds. The bond formation generates heat, which hasbeen a drawback to the original QuikClot® brand hemostatic agent. Newerversions of the product have been developed by Z-Medica that havereduced and eliminated the exothermic reaction.

Other examples of suitable biologically absorbable materials withhemostatic or even wound healing effects include gelatin, collagen,chitin, chitosan, alginate, cellulose, polyglycolic acid, polyaceticacid and mixtures thereof. It will be understood that various formsthereof, such as linear or cross-linked forms, salts, esters and thelike may also be used as the biologically absorbable material to beincluded in the haemostatic powder of the invention.

“Biologically absorbable” is a term which in the present context is usedto describe that the materials of which the said powder are made can bedegraded in the body to smaller molecules having a size which allowsthem to be transported into the blood stream. By said degradation andabsorption the materials will gradually be removed from the site ofapplication. For example, denatured gelatin can be degraded byproteolytic tissue enzymes to absorbable smaller molecules, whereby thedenatured gelatin powder when applied in tissues typically is absorbedwithin about 3-6 weeks and when applied on bleeding surfaces and mucousmembranes typically within 3-5 days.

TABLE 1 Hemostatic and anti-fibrinolytic agents Pro-thrombin and/orCryoprecipitate Chymostatin thrombin Fibrinogen and/or fibrin Freshfrozen plasma Gabexate Factor V and/or Va Fibronectin Zeolites FactorVII and/or VIIa Calcium ions Gelatin Factor VIII and/or VIIIaDesmopressin Collagen Factor IX and/or IXa Tranexamic acid Chitin FactorX and/or Xa Aminocaproic acid Chitosan Factor XI and/or XIa AprotininAlginate Factor XII and/or XIIa Pepstatin Cellulose Factor XIII and/orXIIIa Leupeptin Polyglycolic acid Prothrombin complex AntipainPolyacetic acid concentrate

Wound Healing Promoting Agents

In one embodiment, the device according to the present invention is awound healing device. The wound healing device may thus be imprintedwith wound healing or wound healing promoting agents. A wound healingagent may be an agent that accelerates the wound healing process.

The wound healing device described herein may be used as a medicament.Accordingly, in a further aspect the present invention relates to amethod of promoting wound healing in a patient in need thereof, saidmethod comprising printing a pharmaceutical composition as definedherein onto a device, and using the device to promote wound healing.

Below are listed non-limiting examples of wound healing agents that inone embodiment may be included in the composition that is printed ontothe device of the present invention.

Wound healing agents may be present on the device alone, may be combinedor used together or in coordination with e.g. an antibiotic, antifungal,or antiviral substance or substances to accelerate the healing of soresor other infection-damaged tissue simultaneously or sequentially withthe treatment of the underlying infection.

Further, growth factors to promote healing may also be employed in thecomposition for printing onto the device to promote wound healing.

Adrenaline or other substances capable of constricting blood vesselsthereby reducing local blood flow may also be employed in thecomposition for printing onto the device to promote wound healing.Factors that trigger vasoconstriction can be of exogenous origin, suchas medication and endogenous as well, as a response from the bodyitself. Examples of medications include: anti-histamines such as H1receptor antagonists including Diphenhydramine, Loratadine, Meclizineand Quetiapine; inhibitors of histamine release such as mast cellstabilizers including Cromoglicate (cromolyn) and Nedocromil; caffeine;decongestants such as Ephedrine, Oxymetazoline, Phenylephrine,Pseudoephedrine, Tramazoline, phenylpropanolamine (PPA) andXylometazoline that work on adrenoreceptor al.

Active wound healing compounds can be combined with or usedsimultaneously or sequentially with other tissue healing promoters, suchas epidermal growth factor, fibroblast growth factor, platelet derivedgrowth factor, transforming growth factor alpha, transforming growthfactor beta, and insulin-like growth factor 1 (Brunt, J. V., andTilansner, A., Biotechnology 6:25-30 (1988)) to promote a more rapidhealing of damaged tissue.

It is also useful to imprint the device according to the invention withcorticosteroid and anti-inflammatory agents to accelerate the healing oflesions in patients suffering from allergic or inflammatory processes,since steroids are known to slow the healing of wounds.

The following compounds can be printed onto the surface of the deviceaccording to the present invention in a method for the treatment ofwounds. These include, but are not limited to: allantoin, retinoic acid,aloe vera, glycine, vitamin A, the B vitamins, especially nicotinamide,vitamins C and E, antibacterial agents (e.g., quaternary ammoniumcompounds, bacitracin, neomycin and polymyxin), comfrey rootpreparations, platelets and/or platelet extracts, ribonucleosides,proline, lysine, elastin, glycosaminoglycans, spermidine, spermine,putrescine, angiogenic factors, zinc, alpha-1 antitrypsin, SLPI(Secretory Leukocyte Protease Inhibitor), and various peptide growthfactors such as the somatomedins, Iamin, EGF (epidermal growth factor),IGF1/2 (insulin-like growth factor 1 or 2), PDGF (platelet derivedgrowth factor), FGF (fibroblast growth factor), TGF (transforming growthfactor), MDGF (macrophage-derived growth factor), NGF (neuron growthfactor), PDECGF (Platelet Derived Endothelial Cell Growth Factor), KGF(Keratinocyte Growth Factor), and TNF (Tumor Necrosis Factor). Thepharmaceutically active device of the invention may also be used inconjunction with synthetic skin in treating burns and other wounds, andin supporting the healing of skin or corneal transplants.

Antimicrobial agents may be selected from bactericidal or bacteriostaticagents, such as antibiotics and sulphonamides, antiviral compounds,antimycotic agents and anti-infectives. Antibiotics may be selected frome.g. β-lactams, penicillins, cephalosporins, monobactams, macrolides,polymyxins, tetracyclines, chloramphenicol, thrimethoprim,aminoglycosides, clindamycin, and metronidazole; sulphonamides may as anexample be selected from sulphadimidine or sulphadimethoxin; antimycoticagents may be selected from amphotericin B, ketoconazol and miconazol;and antiviral agent from idoxuridine and azidothymidin. Suitableantiinfectives may as an example be selected from halogens,chlorohexidine and quarternary ammonium compounds. Other examples ofbactericidal or bacteriostatic compounds include silver ions, inparticular in the form of silver ion complexes.

Medical or veterinary indications for the use of the invention include,but are not limited to the following situations. The pharmaceuticalcompositions can be used to accelerate the healing of mechanical woundsor abrasions of the skin or other tissues which are exposed bymechanical injury to the skin or gastrointestinal mucosa of the body.The invention can also be used to accelerate the healing of burnsinflicted upon the skin, and any underlying tissues which may be exposedby such injury. The burns may be those caused by heat, ionizingradiation, ultraviolet radiation including sunlight, electricity, orchemical substances.

In one embodiment, the pharmaceutically active device according to thepresent invention is also useful in conditions in which normal woundhealing is impaired. Examples of types of wounds that heal poorly orslowly include venous stasis ulcers, decubitus ulcers, and cutaneous andalimentary tract wounds, or ulcers in patients with diabetes, and inpatients subjected to irradiation, cancer chemotherapy (e.g. withadriamycin or cyclophosphamide), and topical or systemicanti-inflammatory glucocorticosteriods.

Further, the compositions may be used to accelerate the healing ofsurgical incisions in any part of the body, external or internal, intowhich device according to the present invention may be introduced. Thecompositions can also be used to accelerate the healing of ischemiculcers, pressure sores, bed sores, or ulcers caused by diabetes or otherdisease processes.

TABLE 2 Wound healing agents Adrenaline Platelets and/or β-lactamsplatelet extracts Diphenhydramine Ribonucleosides Penicillins LoratadineProline Cephalosporins Meclizine Lysine Monobactams Quetiapine ElastinMacrolides Cromoglicate (cromolyn) Glycosaminoglycans PolymyxinsNedocromil Spermidine Tetracyclines Caffeine Spermine ChloramphenicolEphedrine Putrescine Thrimethoprim Oxymetazoline Angiogenic factorsAminoglycosides Phenylephrine, Zinc Clindamycin PseudoephedrineSomatomedins Metronidazole Tramazoline Lamin SulphadimidinePhenylpropanolamine FGF Sulphadimethoxin (PPA) Xylometazoline PDGFAmphotericin B Corticosteroid TGF Ketoconazol Allantoin IGF MiconazolRetinoic acid EGF Idoxuridine Aloe vera MDGF Azidothymidin Glycine NGFHalogens Vitamin A KGF Chlorohexidine The B vitamins, especially TNFSilver ions nicotinamide Vitamin C PDECGF alpha-1 antitrypsin Vitamin EBacitracin SLPI Comfrey root preparations Neomycin Quaternary ammoniumPolymyxin compounds

Adhesive Agents

Suitable agents, which may improve the adhesive properties (or thetackiness) of the composition are well-known to the person skilled inthe art. One class of suitable agents includes saccharides, such asmonosaccharides, disaccharides, oligosaccharides, polysaccharides, andcombinations thereof.

When used herein the term “saccharide”, as well as the terms“monosaccharide”, “disaccharide”, “oligosaccharide” and“polysaccharide”, also encompasses derivatives thereof, such assaccharides comprising one or more aminosugar units. In the presentcontext, an aminosugar unit is a sugar unit wherein at least one of thehydroxy groups available in the sugar unit has been substituted by anamino group or an alkanoylated amino group such as an acetylated aminogroup. Accordingly, it will be understood that saccharides containingone or more glucosamine and/or N-acetylglucosamine unit(s) are alsoencompassed by the above-mentioned terms. Apart from the aminosugarunits, the saccharide may contain unsubstituted sugar units or sugarunits substituted with e.g. alkoxy (such as 2,3-dimethylglucose) oracyloxy.

Specific examples of monosaccharides include glucose, mannose, fructose,threose, gulose, arabinose, ribose, erythrose, lyxose, galactose,sorbose, altrose, tallose, idose, rhamnose, allose, and derivativesthereof, e.g. pentosamines, hexosamines, such as glucosamine orN-acetylglucosamine, and glucoronic acid. In particular glucose ispreferred.

Specific examples of disaccharides include sucrose, maltose, lactose,cellubiose as well as derivatives thererof. In particular sucrose ispreferred.

Specific examples of polysaccharides include glycogen, chitin, chitosan,starch such as potato starch, as well as combinations thereof. Specificexamples of polysaccharide derivatives include glycosaminoglycans suchas chondroitin, chondroitin sulfate, hyaluronic acid, dermatan sulfateand keratan sulfate; aminated dextrans including DEAE-dextran; aminatedstarch, aminated glycogen, aminated cellulose, aminated pectin, andsalts, complexes, derivatives and mixtures thereof.

In an interesting embodiment of the invention, the composition furthercomprises an agent which improves the adhesive properties of saidcomposition, where said agent is selected from the group consisting ofglucose, sucrose, and a mixture thereof.

Other examples of agents which improve the adhesive properties of thecomposition include hydrocarbon resins, rosin resins and terpene resins.Hydrocarbon resins are commercially available under the tradenamesEscorez® from ExxonMobil; Regalite®, Piccotac® and Picco® from Eastman;Indopol® from BP or Arkon®. Examples of rosin esters include esters ofhydrogenated wood rosin e.g. pentaerythritol ester of hydrogenated woodrosin, esters of partially hydrogenated wood rosin e.g. pentaerythritolesters of partially hydrogenated wood rosin, esters of wood rosin,esters of modified wood rosin, esters of partially dimerized rosin,esters of tall oil rosin, esters of dimerized rosin, and similar rosins,and combinations and mixtures thereof. Such rosin esters arecommercially available under the tradenames Foral®, Foralyn®, Pentalyn®,Permalyn® and Staybelite®.

Further examples of agents which improve the adhesive properties of thecomposition include Gum Karaya, sometimes known as Sterculia gum, GumArabicum, Gum Karrageenan, celluloseethers, such as sodiumcarboxymethylcellulose, Manuba Honey, casein, alginates or fatty acidesters, such as the fatty acid esters disclosed in WO 95/26715, andgecko-like or gecko-inspired medical adhesives.

Thus, in an interesting embodiment of the invention, the compositioncomprises at least one agent which improves the adhesive properties ofthe composition. Evidently, the exact amount of agent may vary dependingon what specific agent is being used, but the composition typicallycomprises 0.1-50% (w/w) of the agent, based on the total weight of thecomposition. Preferably, and in particular when the agent which improvesthe adhesive properties of the composition is a saccharide, thecomposition comprises 1-25% (w/w), such as 5-20% (w/w), e.g. 5-15%(w/w), 5-10% (w/w), or 10-15% (w/w), based on the total weight of thecomposition.

In one embodiment, the pharmaceutical composition according to thepresent invention is printed onto an adhesive surface of a matrixmaterial.

TABLE 3 Adhesive agents Glucose hexosamines aminated dextrans mannoseglucosamine aminated starch fructose N-acetylglucosamine aminatedglycogen threose glucoronic acid aminated cellulose gulose Sucroseaminated pectin arabinose maltose Hydrocarbon resins ribose lactoseRosin resins erythrose cellubiose Terpene resins lyxose glycogen GumKaraya galactose chitin Gum Arabicum sorbose chitosan Gum Karrageenanaltrose starch Sodium carboxymethylcellulose tallose chondroitin ManubaHoney idose chondroitin sulfate Casein rhamnose hyaluronic acidAlginates allose dermatan sulfate Fatty acid esters pentosamines keratansulfate Gecko-like adhesive

Surfactant Agents

In another interesting embodiment of the invention, the compositionfurther comprises an agent which improves the surfactant properties ofsaid composition, where said agent is selected from the group consistingof anionic surfactants, cationic surfactants, non-ionic surfactants andsurface active biological modifiers.

Examples of anionic surfactants include surfactants selected from thegroup consisting of potassium laurate, triethanolamine stearate, sodiumlauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates,sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol,phosphatidyl inositol, phosphatidylserine, phosphatidic acid and theirsalts, glyceryl esters, sodium carboxymethylcellulose, bile acids andtheir salts, cholic acid, deoxycholic acid, glycocholic acid,taurocholic acid, glycodeoxycholic acid, and calciumcarboxymethylcellulose. In particular sodium lauryl sulfate ispreferred.

Examples of cationic surfactants include surfactants selected from thegroup consisting of quaternary ammonium compounds, benzalkoniumchloride, cetyltrimethylammonium bromide, chitosans andlauryldimethylbenzylammonium chloride.

Examples of non-ionic surfactants include surfactants selected from thegroup consisting of polyoxyethylene fatty alcohol ethers,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acidesters, sorbitan esters, polyoxyethylene sorbitan esters (such as Tween80 or Tween 20), glycerol monostearate, polyethylene glycols,polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearylalcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylenecopolymers, polaxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxy propylmethylcellulose, noncrystallinecellulose, polysaccharides, starch, starch derivatives,hydroxyethylstarch, polyvinyl alcohol, Pluronic F68 andpolyvinylpyrrolidone.

TABLE 4 Surfactants Potassium laurate Glycodeoxycholic acid Aryl alkylpolyether alcohols Triethanolamine Calcium carboxymethyl-Polyoxyethylene- stearate cellulose polyoxypropylene copolymers Sodiumlauryl sulfate Benzalkonium chloride Polaxamines Sodium dodecylsulfateCetyltrimethylammonium Methylcellulose bromide Alkyl polyoxyethyleneChitosans Hydroxycellulose sulfates Sodium alginateLauryldimethylbenzyl- Hydroxy ammonium chloride propylcellulose Dioctylsodium Polyoxyethylene fatty Hydroxy sulfosuccinate alcohol etherspropylmethyl- cellulose Phosphatidyl glycerol Polyoxyethylene sorbitanNoncrystalline fatty acid esters cellulose Phosphatidyl inositolPolyoxyethylene fatty acid Polysaccharides esters PhosphatidylserineSorbitan esters Starch Phosphatidic acid Polyoxyethylene sorbitan Starchderivatives esters Glyceryl esters Glycerol monostearateHydroxyethylstarch Bile acids and their Polyethylene glycols Polyvinylalcohol salts Cholic acid Polypropylene glycols Polyvinyl- pyrrolidoneDeoxycholic acid Cetyl alcohol Albumin Glycocholic acid Cetostearylalcohol Taurocholic acid Stearyl alcohol

Other Bioactive Agents

Below are listed further non-limiting examples of bioactive agents thatin one embodiment may be included in the composition that is printedonto the surface of the matrix of the present invention.

Analgetics are pharmaceutical that may be used to alleviate pain. Ingeneralanalgetics may belong to one of 3 groups, i) opiodanalgetics, ii)weak non-opiod analgetics and iii) psychopharmacological drugs, lidocainanalogues and antiepileptica. In a preferred embodiment of the presentinvention the analgetic is lidocain.

To further illustrate, antimetabolites which can be formulated in thesubject polymers include, but are not limited to, methotrexate,5-fluorouracil, cytosine arabinoside (ara-C), 5-azacytidine,6-mercaptopurine, 6-thioguanine, and fludarabine phosphate.

Antitumor antibiotics may include but are not limited to doxorubicin,daunorubicin, dactinomycin, bleomycin, mitomycin C, plicamycin,idarubicin, and mitoxantrone.

Vinca alkaloid and epipodophyiotoxins may include, but are not limitedto vincristine, vinblastine, vindesine, etoposide and teniposide.

Nitrosoureas can also be provided including carmustine, lomustine,semustine and streptozocin.

Hormonal therapeutics can also be included in the pharmaceuticalcomposition, such as corticosteriods (cortisone acetate, hydrocortisone,prednisone, prednisolone, methylprednisolone and dexamethasone),estrogens, (diethylstibesterol, estradiol, esterified estrogens,conjugated estrogen, chlorotiasnene), progestins (medroxyprogesteroneacetate, hydroxy progesterone caproate, megestrol acetate),antiestrogens (tamoxifen), aromastase inhibitors (aminoglutethimide),androgens (testosterone propionate, methyltestosterone, fluoxymesterone,testolactone), antiandrogens (flutamide), LHRH analogues (leuprolideacetate), and endocrines for prostate cancer (ketoconazole).

Other compounds which in one embodiment may be included in thecomposition of the present invention include those classified as e.g.investigational drugs, and can include, but are not limited toalkylating agents such as Nimustine AZQ, BZQ, cyclodisone, DADAG,CB10-227, CY233, DABIS maleat, EDMN, Fotemustine, Hepsulfam,Hexamethylmelamine, Mafosamide, MDMS, PCNU, Spiromustine, TA077, TCNUand Temozolomide; antimetabolites, such as acivicin, Azacytidine,5-aza-deoxycytidine, A-TDA, Benzylidene glucose, Carbetimer, CB3717,Deazaguanine mesylate, DODOX, Doxifluridine, DUP-785, 10-EDAM,Fazarabine, Fludarabine, MZPES, MMPR, PALA, PLAC, TCAR, TMQ, TNC-P andPiritrexim; antitumor antibodies, such as AMPAS, BWA770U, BWA773U,BWA502U, Amonafide, m-AMSA, CI-921, Datelliptium, Mitonafide,Piroxantrone, Aclarubicin, Cytorhodin, Epirubicin, esorubicin,Idarubicin, Iodo-doxorubicin, Marcellomycin, Menaril,Morpholinoanthracyclines, Pirarubicin, SM-5887; microtubule spindleinhibitors, such as Amphethinile, Navelbine, and Taxol; thealkyllysophospholipids, such as BM41-440, ET-18-OCH3, andHexacyclophosphocholine; metallic compounds, such as Gallium Nitrate,CL286558, CL287110, Cycloplatam, DWA2114R, NK121, Iproplatin,Oxaliplatin, Spiroplatin, Spirogermanium, and Titanium compounds; novelcompounds such as, for example Aphidoicolin glycinate, Ambazone, BSO,Caracemide, DSG, Didemnin, DMFO, Elsamicin, Espertatrucin, Flavoneacetic acid, HMBA, HHT, ICRF-187, Iododeoxyuridine, Ipomeanol,Liblomycin, Lonidamine, LY186641, MAP, MTQ, Merabarone SK, F104864,Suramin, Tallysomycin, Teniposide, THU, 2721, Toremifene, Trilosane, andzindoxifene.

Antitumor drugs that are radiation enhancers can also be formulated inthe subject controlled release formulation. Examples of such drugsinclude, for example, the chemotherapeutic agents 5′-fluorouracil,mitomycin, cisplatin and its derivatives, taxol, bleomycins,daunomycins, and methamycins.

In one embodiment, the biologically active agent is selected from thegroup consisting of polysaccharides, growth factors, hormones,anti-angiogenesis factors, interferons or cytokines, and pro-drugs. In aparticularly preferred embodiment, the biologically active substance isa therapeutic drug or pro-drug, most preferably a drug selected from thegroup consisting of chemotherapeutic agents and other antineoplastics,antibiotics, anti-virals, anti-fungals, anti-inflammatories,anticoagulants, an antigenic materials.

Further examples of medicaments according to the present invention areantimicrobial agents, analgesics, antiinflammatory agents,counterirritants, coagulation modifying agents, diuretics,sympathomimetics, anorexics, antacids and other gastrointestinal agents,antiparasitics, antidepressants, antihypertensives, anticholinergics,stimulants, antihormones, central and respiratory stimulants, drugantagonists, lipid-regulating agents, uricosurics, cardiacglycosides,electrolytes, ergot and derivatives thereof, expectorants, hypnotics andsedatives, antidiabetic agents, dopaminergic agents, antiemetics, musclerelaxants, parasympathomimetics, anticonvulsants, antihistamines,(3-blockers, purgatives, antiarrhythmics, contrast materials,radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators,antiviral agents, andantineoplastic or cytostatic agents or other agentswith anticancer properties, or a combination thereof. Other suitablemedicaments may be selected from contraceptives and vitamins as well asmicro and macronutrients.

Further bioactive agents which may be comprised in the composition inaccordance with the present invention include, without limitation:antiinfectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelmintics; antiarthritics;antiasthmatic agents; anticonvulsants; antidepressants; antidiureticagents; antidiarrleals; antihistamines; anti inflammatory agents;antimigraine preparations; antinauseants; ahtineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics,antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including calcium channelblockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers; and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins.

Further specific examples of bioactive agents include acebutolol,acetaminophen, acetohydroxamic acid, acetophenazine, acyclovir,adrenocorticoids, allopurinol, alprazolam, aluminum hydroxide,amantadine, ambenonium, amiloride, aminobenzoate potassium, amobarbital,amoxicillin, amphetamine, ampicillin, androgens, anesthetics,anticoagulants, anticonvulsants-dione type, antithyroid medicine,appetite suppressants, aspirin, atenolol, atropine, azatadine,bacampicillin, baclofen, beclomethasone, belladonna,bendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine,betamethasone, bethanechol, biperiden, bisacodyl, bromocriptine,bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan,butabarbital, butaperazine, caffeine, calcium carbonate, captopril,carbamazepine, carbenicillin, carbidopa & levodopa, carbinoxamineinhibitors, carbonic anhydsase, carisoprodol, carphenazine, cascara,cefaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloralhydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine,chlorothiazide, chlorotrianisene, chlorpheniramine, chlorpromazine,chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone,cholestyramine, cimetidine, cinoxacin, clemastine, clidinium,clindamycin, clofibrate, clomiphere, clonidine, clorazepate,cloxacillin, colochicine, coloestipol, conjugated estrogen,contraceptives, cortisone, cromolyn, cyclacillM, cyclandelate,cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine,cyproheptadine, danazol, danthron, dantrolene, dapsone,dextroamphetamine, dexamethasone, dexchlorpheniramine, dextromethorphan,diazepan, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal,digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramine,diphenidol, diphenoxylate & atrophive, diphenylopyraline, dipyradamole,disopyramide, disulfuram, divalporex, docusate calcium, docusatepotassium, docusate sodium, doxyloamine, dronabinol ephedrine,epinephrine, ergoloidmesylates, ergonovine, ergotamine, erythromycins,esterified estrogens, estradiol, estrogen, estrone, estropipute,etharynic acid, ethchlorvynol, ethinyl estradiol, ethopropazine,ethosaximide, ethotoin, fenoprofen, ferrous fumarate, ferrous gluconate,ferrous sulfate, flavoxate, flecamide, fluphenazine, fluprednisolone,flurazepam, folic acid, furosemide, gemfibrozil, glipizide, glyburide,glycopyrrolate, gold compounds, griseofiwin, guaifenesin, guanabenz,guanadrel, guanethidine, halazepam, haloperidol, hetacillin,hexobarbital, hydralazine, hydrochlorothiazide, hydrocortisone(cortisol), hydroflunethiazide, hydroxychloroquine, hydroxyzine,hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol,iron-polysaccharide, isoetharine, isoniazid, isopropamide isoproterenol,isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole, lactulose,levodopa, lincomycin liothyronine, liotrix, lithium, loperamide,lorazepam, magnesium hydroxide, magnesium sulfate, magnesiumtrisilicate, maprotiline, meclizine, meclofenamate, medroxyproyesterone,melenamic acid, melphalan, mephenyloin, mephobarbital, meprobamate,mercaptopurine; mesoridazine, metaproterenol, <RTI metaxalone,methamphetamine, methaqualone, metharbital, methenamine, methicillin,methocarbamol, methotrexate, methsuximide, methyclothinzide,methylcellulos, methyldopa, methylergonovine, methylphenidate,methylprednisolone, methysergide, metoclopramide, metolazone,metoprolol, metronidazole, minoxidil, mitotane, monamine oxidaseinhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcoticanalgesics, neomycin, neostigmine, niacin, nicotine, nifedipine,nitrates, nitrofurantoin, nomifensine, norethindrone, norethindroneacetate, norgestrel, nylidrin, nystatin, orphenadrine, oxacillin,oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase,pantothenic acid, papaverine, para-aminosalicylic acid, paramethasone,paregoric, pemoline, penicillamine, penicillin, penicillin-v,pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine,phenobarbital, phenolphthalein, phenprocoumon, phensuximide,phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine,phenyloin, pilocarpine, pindolol, piper acetazine, piroxicam, poloxamer,polycarbophil calcium, polythiazide, potassium supplements, pruzepam,prazosin, prednisolone, prednisone, primidone, probenecid, probucol,procainamide, procarbazine, prochlorperazine, procyclidine, promazine,promethazine, propantheline, propranolol, pseudoephedrine, psoralens,syllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol,quinethazone, uinidine, quinine, ranitidine, rauwolfia alkaloid,riboflavin, rifampin, ritodrine, alicylates, scopolamine, secobarbital,senna, sannosides a & b, simethicone, sodium bicarbonate, sodiumphosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine,sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole,sulindac, talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate,teracyclines, thiabendazole, thiamine, thioridazine, thiothixene,thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocamide,tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone,trianterene, triazolam, trichlormethiazide, tricyclic antidepressants,tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl,trimeprazine, trimethobenzamine, trimethoprim, tripclennamine,triprolidine, valproic acid, verapamil, vitamin A, vitamin B-12, vitaminC, vitamin D, vitamin E, vitamin K, xanthine, and the like.

Further examples of medicaments include, but are not limited to,antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramineand dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine,morphine, dihydromorphone, oxycodone, etc.), anti-inflammatory agents(e.g., naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen,aspirin, sulindac), gastrointestinals, and anti-emetics (e.g.,metoclopramide), anti-epileptics (e.g., phenyloin, meprobamate andnitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem andnicardipine), anti-tussive agents and expectorants (e.g., codeinephosphate), anti-asthmatics (e.g. theophylline), anti-spasmodics (e.g.atropine, scopolamine), hormones (e.g., insulin, heparin), diuretics(e.g., ethacrynic acid, bendroflumethiazide), anti-hypotensives (e.g.,propranolol, clonidine), bronchodilators (e.g., albuterol),anti-inflammatory steroids (e.g., hydrocortisone, triamcinolone,prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals,hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives,decongestants, laxatives, antacids, vitamins, stimulants (includingapetite suppressants such as phenylpropanolamine). The above list is notmeant to be exclusive.

Other types of medicaments include flurazepam, nimetazepam, nitrazepam,perlapine, estazolam, haloxazolam, sodium valproate, sodiumcromoglycate, primidone, alclofenac, perisoxal citrate, clidanac,indomethacin, sulpyrine, flufenamic acid, ketoprofen, sulindac,metiazinic acid, tolmetin sodium, fentiazac, naproxen, fenbufen,protizinic acid, pranoprofen, flurbiprofen, diclofenac sodium, mefenamicacid, ibuprofen, aspirin, dextran sulfate, carindacillin sodium, and thelike.

The medicament may be in the form of a physiologically activepolypeptide, which is selected from the group consisting of insulin,somatostatin, somatostatin derivatives, growth hormone, prolactin,adrenocorticotrophic hormone, melanocyte stimulating hormone,thyrotropin releasing hormone, its salts or its derivatives, thyroidstimulating hormone, luteinizing hormone, follicle stimulating hormone,vasopressin, vasopressin derivatives, oxytocin, carcitonin, parathyroidhormone, glucagon, gastrin, secretin, pancreozymin, cholecystokinin,angiotensin, human placentalactogen, human chorionic gonadotropin,enkephalin, enkephalin derivatives, endorphin, interferon (in one ormore of the forms alpha, beta, and gamma), urokinase, kallikrein,thymopoietin, thymosin, motilin, dynorphin, bombesin, neurotensin,caerulein, bradykinin, substance P, kyotorophin, nerve growth factor,polymyxin B, colistin, gramicidin, bacitracin, bleomycin andneocarzinostatin.

Furthermore, the bioactive agent may be a polysaccharide, such asheparin, an antitumor agent such as lentinan, zymosan and PS-K(krestin), anaminoglycoside such as e.g. gentamycin, streptomycin,kanamycin, dibekacin, paromomycin, kanendomycin, lipidomycin,tobramycin, amikacin, fradiomycin and sisomicin, a beta-lactamantibiotic, such as e.g. a penicillin, such as e.g. sulbenicillin,mecillinam, carbenicillin, piperacillin and ticarcillin, thienamycin,and cephalosporins such ascefotiam, cefsulodine, cefmenoxime,cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoximeandmoxalactam, or a nucleic acid drug such as e.g. citicoline andsimilar antitumor agents, for example cytarabine and 5-FU(5-fluorouracil).

Certain monomeric subunits of the present invention may exist inparticular geometric or stereoisomeric forms. The present inventioncontemplates all such compounds, including cis- and trans-isomers, R-and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

For the purposes of this application, unless expressly noted to thecontrary, a named amino acid shall be construed to include both the D orL stereoisomers, preferably the L stereoisomer.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

Antibiotic Agents

An antibiotic is a chemotherapeutic agent that inhibits or abolishes thegrowth of micro-organisms, such as bacteria, fungi, or protozoa. Belowis a list of antibiotic agents that in one embodiment may be comprisedin the pharmaceutical composition to be printed onto the surface of amatrix material.

Antibiotics are well known to those of skill in the art, and include,for example, penicillins, cephalosporins, tetracyclines, ampiciflin,aureothicin, bacitracin, chloramphenicol, cycloserine, erythromycin,gentamicin, gramacidins, kanamycins, neomycins, streptomycins,tobramycin, and vancomycin. Further antibiotic agents are listed inTable 5 below:

TABLE 5 Antibiotic agents Amikacin, Anisomycin, Apramycin, Azithromycin,Blasticidine, Brefeldin A, Butirosin, Butirosin A, Chloramphenicol,Chlortetracycline hydrochloride, Clindamycin 2-phosphate, Clindamycinhydrochloride, Clotrimazole, Cycloheximide, Demeclocyclinehydrochloride, Dibekacin sulfate salt, Dihydrostreptomycinsesquisulfate, Dihydrostreptomycin solution, Doxycycline hyclate,Duramycin, Emetine dihydrochloride hydrate, Erythromycin, TemephosPESTANAL ®, Erythromycin estolate, Erythromycin ethyl succinate,Erythromycin stearate, Fusidic acid sodium salt, Fusidic acid sodiumsalt, G 418 disulfate salt, Gentamicin solution, Gentamicin sulfate,Gentamicin-Glutamine solution, Helvolic acid, Hygromycin B, Hygromycin Bsolution, Josamycin, Josamycin solution, Kanamycin B sulfate salt,Kanamycin disulfate salt, Kanamycin monosulfate, Kanamycin solution,Kirromycin, Lincomycin hydrochloride, Lincomycin standard solution,Meclocycline sulfosalicylate salt, Mepartricin, Midecamycin, Minocyclinehydrochloride, Neomycin solution, Neomycin trisulfate salt hydrate,Neomycin B, Netilmicin sulfate salt, Nitrofurantoin crystalline,Nourseothricin sulfate, Oleandomycin phosphate salt, Oleandomycintriacetate, Oxytetracycline dehydrate, Oxytetracycline hemicalcium salt,Oxytetracycline hydrochloride, Paromomycin sulfate salt, Puromycindihydrochloride, Rapamycin, Ribostamycin sulfate salt, Rifampicin,Rifamycin SV sodium salt, Rosamicin, Sisomicin sulfate salt,Spectinomycin dihydrochloride hydrate, Spectinomycin dihydrochloridepentahydrate, Spectinomycin standard solution, Spiramycin, Spiramycinsolution (mixture of spiramycin I, II and III), Streptomycin solution,Streptomycin sulfate salt, Tetracycline, Tetracycline hydrochloride,Thiamphenicol, Tobramycin, Tobramycin sulfate salt, Tunicamycin A₁,Tunicamycin C₂, Tunicamycin, Tylosin solution, Tylosin tartrate,Viomycin sulfate salt, Virginiamycin M₁, (S)-(+)-Camptothecin,10-Deacetylbaccatin III, 5-Azacytidine, 7- Aminoactinomycin D,8-Quinolinol crystalline, 8-Quinolinol hemisulfate salt crystalline, 9-Dihydro-13-acetylbaccatin III, Aclarubicin, Aclarubicin hydrochloride,Actinomycin D, Actinomycin D□Mannitol, Actinomycin I, Actinomycin V,Aphidicolin, Bafilomycin A1, Bleomycin sulfate, Capreomycin sulfate,Chromomycin A₃, Cinoxacin, Ciprofloxacin, cis-Diammineplatinum(II)dichloride, Coumermycin A1, Cytochalasin B,Cytochalasin, Dacarbazine, Daunorubicin hydrochloride, Distamycin Ahydrochloride, Doxorubicin hydrochloride, Echinomycin, Enrofloxacin,Etoposide, Flumequine, Formycin A, Fumagillin, Ganciclovir, Gliotoxin,Lomefloxacin hydrochloride, Metronidazole, Mithramycin A, Mitomycin C,Nalidixic acid, Nalidixic acid sodium salt, Netropsin dihydrochloridehydrate, Nitrofurantoin, Nogalamycin, Nonactin, Novobiocin sodium salt,Ofloxacin, Oxolinic acid, Paclitaxel, Phenazine methosulfate,Phleomycin, Pipemidic acid, Rebeccamycin, Sinefungin, Streptonigrin,Streptozocin, Succinylsulfathiazole, Sulfadiazine, Sulfadimethoxine,Sulfaguanidine, Sulfamethazine, Sulfamonomethoxine, Sulfanilamide,Sulfaquinoxaline sodium salt, Sulfasalazine, Sulfathiazole sodium salt,Trimethoprim, Trimethoprim lactate salt, Tubercidin, 5-Azacytidine,Cordycepin, Formycin A, Tubercidin, (+)-6-Aminopenicillanic acid, 7-Aminodesacetoxycephalosporanic acid, Amoxicillin, Ampicillin, Ampicillinsodium salt, Ampicillin trihydrate, Azlocillin sodium salt, Bacitracin,Bacitracin zinc salt, Carbenicillin disodium salt, Cefaclor, Cefamandolelithium salt, Cefamandole nafate, Cefamandole sodium salt, Cefmetazolesodium salt, Cefoperazone sodium salt, Cefotaxime sodium salt,Cefsulodin sodium salt, Cefsulodin sodium salt hydrate, Ceftriaxonesodium salt, Cephalexin hydrate, Cephalosporin C zinc salt, Cephalothinsodium salt, Cephapirin sodium salt, Cephradine, Cloxacillin sodiumsalt, Cloxacillin sodium salt monohydrate, D-(□)-Penicillaminehydrochloride, D-Cycloserine, Dicloxacillin sodium salt monohydrate,D-Penicillamine, Econazole nitrate salt, Ethambutol dihydrochloride,Lysostaphin, Moxalactam sodium salt, Nafcillin sodium salt monohydrate,Nikkomycin, Nikkomycin Z, Nitrofurantoin, Oxacillin sodium salt,Penicillic acid, Penicillin G potassium salt, Penicillin G sodium salthydrate, Penicillin G sodium salt, Phenethicillin potassium salt,Phenoxymethylpenicillinic acid potassium salt, Phosphomycin disodiumsalt, Pipemidic acid, Piperacillin sodium salt, Piperacillin sodiumsalt, Ristomycin monosulfate, ristocetin A, Ristocetin B, Ristomycinmonosulfate, Vancomycin hydrochloride, 2- Mercaptopyridine N-oxidesodium salt, 4-Bromocalcimycin A23187, Alamethicin, Amphotericin B,Calcimycin A23187, Calcimycin A23187 hemi(calcium-magnesium) salt,Calcimycin A23187 hemicalcium salt, Calcimycin A23187 hemimagnesiumsalt, Chlorhexidine diacetate salt monohydrate, Chlorhexidine diacetatesalt hydrate, Chlorhexidine digluconate, Clotrimazole, Colistin sodiummethanesulfonate, Colistin sulfate salt, Econazole nitrate salt,Hydrocortisone 21-acetate VETRANAL ®, Filipin complex, Gliotoxin,Gramicidin A, Gramicidin, Gramicidin, mixture of gramicidins A, B, C,and D, Ionomycin calcium salt, Lasalocid A sodium salt, Lonomycin Asodium salt, Monensin sodium salt, N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride, Narasin, Nigericin sodium salt,Nisin, Nonactin, Nystatin, Phenazine methosulfate, Pimaricin, PolymyxinB, Polymyxin B sulfate salt, DL- Penicillamine acetone adducthydrochloride monohydrate, Praziquantel, Salinomycin, Surfactin,Valinomycin, (+)-Usnic acid, (±)-Miconazole nitrate salt,(S)-(+)-Camptothecin, 1- Deoxymannojirimycin hydrochloride,1-Deoxymannojirimycin hydrochloride, 1-Deoxynojirimycin hydrochloride,2-Heptyl-4-hydroxyquinoline N-oxide, Cordycepin, 1,10-Phenanthrolinehydrochloride monohydrate, 6-Diazo-5-oxo-L-norleucine, 8-Quinolinol,8-Quinolinol hemisulfate salt, Antimycin A, Antimycin A₁, Antimycin A₂,Antimycin A₃, Antipain, Ascomycin, Azaserine, Bafilomycin A1,Bafilomycin B1, Cerulenin, Chloroquine diphosphate salt, Cinoxacin,Ciprofloxacin, Mevastatin, Concanamycin A, Concanamycin C, CoumermycinA1 , L(+)-Lactic acid, Cyclosporin A, Econazole nitrate salt,Enrofloxacin, Etoposide, Flumequine, Formycin A, Furazolidone, Fusaricacid, Geldanamycin, Gliotoxin, Gramicidin A, Gramicidin C, Gramicidin,mixture of gramicidins A, B, C, and D, Herbimycin A, Indomethacin,Irgasan Lomefloxacin hydrochloride, Mycophenolic acid, Myxothiazol,N-(6-Aminohexyl)-5-chloro-1- naphthalenesulfonamide hydrochloride,Nalidixic acid, Nalidixic acid sodium salt, Netropsin dihydrochloridehydrate, Niclosamide, Nikkomycin, N-Methyl-1-deoxynojirimycin,Nogalamycin, Nonactin, Novobiocin sodium salt, Ofloxacin, Oleandomycintriacetate, Oligomycin, Oligomycin A, Oligomycin B, Oligomycin C,Oxolinic acid, Piericidin A, Pipemidic acid, Radicicol, Rapamycin,Rebeccamycin, Sinefungin, Staurosporine, Stigmatellin,Succinylsulfathiazole, Sulfadiazine, Sulfadimethoxine, Sulfaguanidine,Sulfamethazine, Sulfamonomethoxine, Sulfanilamide, Sulfaquinoxalinesodium salt, Sulfasalazine, Sulfathiazole sodium salt, Sulfathiazolesodium salt, Triacsin C, Trimethoprim, Trimethoprim, Trimethoprimlactate salt, Vineomycin A₁, Tectorigenin, Paracelsin.

Indicators Contained in the Pharmaceutical Composition

In one embodiment, the fluid or liquid composition to be printed onto amatrix material according to the present invention comprises one or moreindicators. An indicator as used herein means a detector such as achemical detector capable of detecting the presence of a condition oranother chemical.

Detection of a condition by the indicator as printed onto the sponge mayoccur by e.g. a colour reaction, whereby one condition causes thecomposition comprising the indicator to acquire a certain colour changeand another condition causes the composition comprising the indicator toacquire another certain colour change or alternatively no colour change.A colour change or the absence of a colour change is thus indicative ofa certain condition. A colour reaction is a type of a visual indicator.

Thus, the indicator may in one embodiment be a visual indicator, such asa colour indicator.

In one embodiment, the indicator is a pH indicator, capable of revealingthe pH condition in the skin or wound contacting area of the matrixmaterial according to the present invention, selected from thenon-limiting group of Bicarbonate indicator, Gentian violet (Methylviolet), Leucomalachite green, Thymol blue, Methyl yellow, Bromophenolblue, Congo red, Methyl orange, Bromocresol green, Methyl red, Methylred/Bromocresol green, Azolitmin, Bromocresol purple, Bromothymol blue,Phenol red, Neutral red, Naphtholphthalein, Cresol Red, Phenolphthalein,Thymolphthalein, Alizarine Yellow R, and a universal indicator. Auniversal indicator is a pH indicator that transitions through numbers3-12 on the pH chart. A universal indicator is typically composed ofwater, methanol, propan-1-ol, phenolphthalein sodium salt, methyl redsodium salt, bromothymol blue monosodium salt, and thymol bluemonosodium salt.

It follows that any pH indicators may be used alone or in combination inthe composition according to the present invention.

A blood type (also called a blood group) is a classification of bloodbased on the presence or absence of inherited antigenic substances onthe surface of red blood cells (RBCs). These antigens may be proteins,carbohydrates, glycoproteins, or glycolipids, depending on the bloodgroup system, and some of these antigens are also present on the surfaceof other types of cells of various tissues. Several of these red bloodcell surface antigens, that stem from one allele (or very closely linkedgenes), collectively form a blood group system. Blood types areinherited and represent contributions from both parents. A total of 30human blood group systems are now recognized by the InternationalSociety of Blood Transfusion (ISBT).

The indicator may an indicator of the blood type of an individual,capable of detecting the blood type of the ABO-system. According to thissystem, a person has the blood type of either type A (AO or AA), B (BOor BB), AB or O (O). Type A has the A antigen, and anti-B antibodies;Type B has the B antigen, and anti-A antibodies; Type AB has the A and Bantigens, and no antibodies; Type O has no antigens, and both anti-A andanti-B antibodies.

The indicator may also be an indicator of the blood type of anindividual, capable of detecting the blood type of the rhesus-system.According to this system, a person has the blood type of either rhesusnegative or rhesus positive.

In one embodiment, the indicator is a blood type indicator, capable ofrevealing the blood type of an individual by contacting a wound areawith the matrix material according to the present invention, such as anagglutination-type reaction. Agglutination-type reactions are known frome.g. the Coombs test.

An indicator may also one that is capable of detecting any type ofdisease or condition, such as the following non-limiting examples:Allergy, Autoimmune Diseases, Blood Diseases, Cancer, Blood Cholesterol,Diabetes, Genetic Testing, Drug Screening, Environmental Toxins,Nutrition, Gastrointestinal Diseases, Heart Diseases, Hormones,Metabolism (sodium, potassium, chloride, bicarbonate, blood ureanitrogen (BUN), magnesium, creatinine, glucose and/or calcium),Infectious Diseases, Kidney Diseases, Liver Diseases, SexuallyTransmitted Diseases (STD's) and Thyroid Disease.

The one or more bioactive agents disclosed herein above may be comprisedin the same fluid or liquid composition contained in the same reservoirand expelled from the same print head comprising one or more nozzles, orthe one or more bioactive agents may be comprised in separate fluid orliquid compositions contained in separate reservoirs and expelled fromseparate print heads each comprising one or more nozzles or expelledfrom different channels of the same print head.

In one embodiment, two or more fluid or liquid compositions eachcomprising one or more bioactive agents may be imprinted at the same ordifferent discrete positions on the surface of said matrix material.

Incompatible Agents or Bioactive Agents in Separate Compositions

In one embodiment, the present invention relates to a matrix materialcomprising a surface and a plurality of open and interconnected cells,wherein the surface of said matrix comprises two differentpharmaceutical compositions, wherein the two pharmaceutical compositionscomprises different agents or bioactive agents which are incompatible,and wherein said two pharmaceutical compositions are printed onto saidsurface in discrete and non-overlapping locations.

Two or more different fluid or liquid compositions each comprising atleast one agent or bioactive agent may thus be imprinted at differentand discrete positions on the surface of a matrix material. This isespecially relevant when said agents or bioactive agents are notcompatible when comprised in the same fluid or liquid composition forvarious reasons, and when said incompatible agents or bioactive agentsmay be printed separately but in close proximity to each other, forexample in alternating positions on the surface of a matrix material.Printing of a fluid or liquid composition in individual and discretelocations with very high precision is possible only with the printtechnique; it is not possible using e.g. the spray-technique or anyother conventional technique known at present.

Incompatibility may arise from the two agents or bioactive agentsinappropriately interacting when in contact in the same position ineither a fluid or liquid composition or on the surface of a matrixmaterial. Thus, interaction between substances or bioactive agent may becontrolled and postponed until desired with the printing technology.

In one embodiment, interaction of two agents or bioactive agents capableof interacting with each other, which are printed in close proximity toeach other on the surface of a matrix material according to the presentinvention, is initiated by wetting of the matrix material, bycompression of the matrix material, by contacting or rubbing the surfaceof the matrix material against another surface or any other means.

The two or more fluid or liquid compositions may each comprise one agentor bioactive agent which may be an enzyme and its substrate,respectively; an enzyme, its substrate and a catalyst, respectively; onecomponent of a two-component glue and another component of saidtwo-component glue; or thrombin and fibrinogen.

In a particular embodiment the two individual compositions each compriseone component of a two-component glue, such as a surgical glue, whichconstitute two different fluid or liquid compositions that are printedonto separate and discrete positions of the surface of a matrixmaterial.

The Matrix Material of the Device

The device according to the present invention in a preferred embodimentcomprises a matrix consisting of a matrix material, onto which acomposition is printed on the surface of the matrix material.

In one embodiment, the matrix material comprises one or more polymersselected form the group consisting of collagen, gelatin, polyurethane,polysiloxanes (silicone), hydrogels, polyacrylamides, chitosan, sodiumpolyacrylate, agarose, alginates, xanthan gum, guar gum, arabic gum,agar gum, Locust Bean gum, Carrageenan gum, Xanthan gum, Karaya gum,tragacanth gum, Ghatti gum, Furcelleran gum, chitin, cellulose,methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, hyaluronic acid,pectin, starch, glycogen, pentosans, polyoxyethylene, polyAMPS(poly(2-acrylamido-2-methyl-1-propanesulfonic acid),polyvinylpyrrolidone, polyvinyl alcohol, polyglycolic acid, polyaceticacid, acrylate polymers, polyhydroxyalkyl acrylates, methacrylates,polyvinyl lactams, polyvinyl alcohols, polyoxyalkylenes,polyacrylamides, polyacrylic acid, polystyrene sulfonates, synthetichydrocolloids such as N-vinyl-2-pyrrolidone,5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone,3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone,3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone,4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam,N-vinyl-2-caprolactam, hydroxyalkyl acrylates and methacrylates, (suchas 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropylacrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropylmethacrylate), acrylic acid, methacrylic acid, tertiaryamino-methacrylimide, (e.g. trimethylamino-methacrylimide), crotonicacid, pyridine, water soluble amides, (such asN-(hydroxymethyl)acrylamide and -methacrylamide,N-(3-hydroxpropyl)acrylamide, N-(2-hydroxyethyl)methacrylamide,N-(1,1-dimethyl-3-oxabutypacrylamideN-[2-(dimethylamine)ethyl]acrylamide and -methacrylamide,N-[3-(dimethylamino)-2-hydroxylpropyl]methacrylamide, andN-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide); water-solublehydrazine derivatives, (such as trialkylamine methacrylimide, anddimethyl-(2-hydroxypropyl)amine methacrylimide); mono-olefinic sulfonicacids and their salts, (such as sodium ethylene sulfonate, sodiumstyrene sulfonate, 2-acrylamideo-2-methylpropanesulfonic acid),1-vinyl-imidazole, 1-vinyl-indole, 2-vinyl imidazole,4(5)-vinyl-imidazole 2-vinyl-1-methyl-imidazole 5-vinyl-pyrazoline,3-methyl-5-isopropenyl-pyrazole, 5-methylene-hydantoin,3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone,3-methacrylyl-5-methyl-2-oxazolidone, 3-vinyl-5-methyl-2-oxazolidone, 2-and 4-vinyl-pyridine, 5-vinyl-2-methyl-pyridine,2-vinyl-pyridine-1-oxide, 3-isopropenyl-pyridine, 2- and4-vinyl-piperidine, 2- and 4-vinyl-quinoline,2,4-dimethyl-6-vinyl-s-triazine, 4-acrylyl-morpholine, OxidizedRegenerated Cellulose (ORC), poly(lactic-co-glycolic acid) (PLGA),Polylactic acid (PLA), Extracellular matrix (ECM), and mixtures thereof.

In a preferred embodiment of the present invention, the matrix of thedevice is a sponge. In yet another preferred embodiment, the sponge is agelatin-sponge or a collagen-sponge or a gelatin- or collagen-comprisingsponge.

The gelatin typically originates from a porcine source, but mayoriginate from other animal sources, such as from bovine or fishsources. The gelatin may also be synthetically made, i.e. made byrecombinant means.

The collagen typically originates from a bovine source, but mayoriginate from other animal sources. The collagen may also besynthetically made, i.e. made by recombinant means.

The gelatin or collagen matrix may be commercially available.Non-limiting examples of commercially available gelatin or collagenmatrixes include Spongostan, Surgifoam, Surgiflo (all Ferrosan A/S),Collastat (Kendall Co.), Avitene (Avicon Inc.), Surgicel (Johnson &Johnson) and Gelfoam (Pfizer).

In one embodiment of the present invention, the material comprising thematrix has some defined physical characteristics relating to thereconformation rate. The reconformation rate of the matrix materialrefers to the elasticity of the matrix material, and is typicallydetermined by a method based on the rate at which the sponge regains itsoriginal size and shape, as described in Example 1. In one embodiment ofthe invention, the matrix material has a reconformation rate of no morethan 10 seconds, such as no more than 9 seconds, for example no morethan 8 seconds, such as no more than 7 seconds, for example no more than6 seconds, such as no more than 5 seconds, for example no more than 4seconds, such as no more than 3 seconds, for example no more than 3seconds, such as no more than 1 second.

The physical characteristics defining the matrix material may alsorelate to the Compression modulus (or Young's modulus). The modulus is ameasure of the hardness or softness of a material and is equal to stressdivided by strain. Stress is equal to pressure. Strain or deflection isequal to the ratio of the change in thickness to the original thicknessof the material. The lower the modulus, the softer the material. Inshort; the ratio of stress to strain in compression. To test thisproperty, ASTM D695 is the standard test method in the USA, and theanalogous test to measure compressive strength in the ISO system is ISO604.

The modulus of the matrix material according to the present inventionmay be in the range of 0.1-50 GPa, such as 0.1-1, for example 1-2, suchas 2-3, such as 3-4, for example 4-5, such as 5-6, for example, 6-7,such as 7-8, for example 8-9, such as 9-10, for example 10-20, such as20-30, for example 30-40, such as 40-50 GPa.

In one embodiment of the present invention, the pore size of the matrixmaterial has a normal distribution around 0.1-1.0 mm. The pore size maybe less than 10 mm, such as less than 9 mm, for example less than 8 mm,such as less than 7 mm, for example less than 6 mm, such as less than 5mm, for example less than 4 mm, such as less than 3 mm, for example lessthan 2.9 mm, such as less than 2.8 mm, for example less than 2.7 mm,such as less than 2.6 mm, for example less than 2.5 mm, such as lessthan 2.4 mm, for example less than 2.3 mm, such as less than 2.2 mm, forexample less than 2.1 mm, such as less than 2 mm, for example less than1.9 mm, such as less than 1.8 mm, for example less than 1.7 mm, such asless than 1.6 mm, for example less than 1.5 mm, such as less than 1.4mm, for example less than 1.3 mm, such as less than 1.2 mm, for exampleless than 1.1 mm, such as less than 1.0 mm, for example less than 0.9mm, such as less than 0.8 mm, for example less than 0.7 mm, such as lessthan 0.6 mm, for example less than 0.5 mm, such as less than 0.4 mm, forexample less than 0.3 mm, such as less than 0.2 mm, for example lessthan 0.1 mm, such as less than 0.05, for example less than 0.01 mm.

In yet an embodiment, the pore size of the matrix material is in therange of 0.01-0.1 mm, such as 0.1-0.2 mm, for example 0.2-0.3 mm, suchas 0.3-0.4 mm, for example 0.4-0.5 mm, such as 0.5-0.6 mm, for example0.6-0.7 mm, such as 0.7-0.8 mm, for example 0.8-0.9 mm, such as 0.9-1mm, for example 1-1.1 mm, such as 1.1-1.2 mm, for example 1.2-1.3 mm,such as 1.3-1.4 mm, for example 1.4-1.5 mm, such as 1.5-1.6 mm, forexample 1.6-1.7 mm, such as 1.7-1.8 mm, for example 1.8-1.9 mm, such as2-2.1 mm, for example 2.1-2.2 mm, such as 2.2-2.3 mm, for example2.3-2.4 mm, such as 2.4-2.5 mm, for example 2.5-2.6 mm, such as 2.6-2.7mm, for example 2.7-2.8 mm, such as 2.8-2.9 mm, for example 2.9-3 mm,such as 3-4 mm, for example 4-5 mm, such as 5-6 mm, for example 6-7 mm,such as 7-8 mm, for example 8-9 mm, such as 9-10 mm.

In another embodiment of the present invention, the surface of thematrix material has some defined properties relating to the porous oruneven surface of the matrix material. Porosity is a measure of the voidspaces in a material, and is measured as a fraction, between 0-1, or asa percentage between 0-100%. The porosity of the surface may thus relyon the pore size of the material of the matrix.

By modifying the surface properties of the underlying matrix material(hydrophobicity, chemical heterogeneity, roughness), the evaporationprocess of the tiny droplets can be tuned in a definite way.

In one embodiment, the hydrophobicity of the surface of the matrixmaterial may be modulated to increase evaporation. In chemistry,hydrophobicity refers to the physical property of a molecule (known as ahydrophobe) that is repelled from a mass of water. Hydrophobic moleculestend to be non-polar and thus prefer other neutral molecules andnonpolar solvents. Hydrophobic molecules in water often cluster togetherforming micelles. Water on hydrophobic surfaces will exhibit a highcontact angle (meaning that the droplet will make the least possiblecontact area with the surface).

In another embodiment, the roughness of the surface of the matrixmaterial can be modulated to increase evaporation. This may depend onpore size.

In one embodiment, the pharmaceutical composition of the presentinvention comprises the bioactive agent thrombin, as described in detailbelow. The composition is printed onto the surface of the matrix. In apreferred embodiment, the surface of the matrix contains less than 300IU/cm² (international units per square centimeter), such as less than290, for example less than 280, such as 270, for example less than 260,such as less than 250, for example less than 240, such as 230, forexample less than 220, such as less than 210, for example less than 200,such as 190, for example less than 180, such as less than 170, forexample less than 160, such as 150, for example less than 140, such asless than 130, for example less than 120, such as 110, for example lessthan 100 IU/cm², such as less than 95, for example less than 90, such as85, for example less than 80, such as less than 75, for example lessthan 70, such as 65, for example less than 60, such as less than 55, forexample less than 50, such as 45, for example less than 40, such as lessthan 35, for example less than 30, such as 25, for example less than 20,such as less than 15, for example less than 10, such as 5, for exampleless than 1 IU/cm².

In another preferred embodiment, the surface of the matrix containsbetween 1-5 IU/cm², such as 5-10, for example 10-15, such as 15-20, forexample 20-25, such as 25-30, for example 30-35, such as 35-40, forexample 40-45, such as 45-50, for example 50-55, such as 55-60, forexample 60-65, such as 65-70, for example 70-75, such as 75-80, forexample 80-85, such as 85-90, for example 90-95, such as 95-100, forexample 100-110, such as 110-120, for example 120-130, such as 130-140,for example 140-150, such as 150-160, for example 160-170, such as170-180, for example 180-190, such as 190-200, for example 200-210, suchas 210-220, for example 220-230, such as 230-240, for example 240-250,such as 250-260, for example 260-270, such as 270-280, for example280-290, such as 290-300 IU/cm².

In one embodiment of the present invention, different dimensions of thedevice comprising a matrix material may be engaged. Thus, the dimensionsof the matrix material (length, width and height) may be less than 15 cmlong, less than 10 cm wide and less than 2 cm high.

Furthermore, different shapes of the device comprising a matrix materialmay be engaged. Non-limiting examples include a square form, circularform, rectangular form, cubic form, spherical form and pyramid-shapedforms.

Different colors of the device comprising a matrix material may beengaged. Non-limiting examples include red, pink, yellow, blue, green,white, black, brown, purple, orange, grey and turquoise.

In one embodiment, these colours may aide in identifying the deviceaccording to the composition that has been printed onto the surface ofthe matrix material of the device. Thus, for example a purple device maysignal that thrombin is printed onto the gelatin-based sponge of thematrix material of said device.

Different types of the device comprising a matrix material may beengaged. Thus, the device may comprise a sponge, a gel, a bandage, aswab, a dressing and a patch.

The temperature of the matrix material employed in the present inventionmay be adjusted to be within the range of 5-70° C., such as 5-10, forexample 10-15, such as 15-20, for example 20-25, such as 25-30, forexample 30-40, such as 40-50, for example 50-60, such as 60-70° C.

Sterilization of the Matrix or the Device

In one embodiment of the present invention, the device according to thepresent invention comprises a matrix and a pharmaceutical compositionthat has been printed onto the surface of a matrix or a device byprinting, such as printing by any suitable state-of-the-art printingtechnology. The matrix or the device is preferably sterile and containedin a sterile, pre-packaged, ready-to-use container.

The sterilization preferably occurs after the packaging step.Sterilization refers to any process that effectively kills or eliminatestransmissible agents (such as fungi, bacteria, viruses, prions and sporeforms etc.) from e.g. a surface or equipment. Sterilization can beachieved through application of heat, chemicals, irradiation, highpressure or filtration. Heat sterilization include autoclaving (usessteam at high temperatures); radiation sterilization include X-rays,gamma rays, UV light and subatomic particles; chemical sterilizationinclude using ethylene oxide gas, ozone, chlorine bleach,glutaraldehyde, formaldehyde, ortho phthalaldehyde, hydrogen peroxideand peracetic acid.

The Composition to be Printed onto the Matrix of Device

Besides comprising at least one agent or bioactive agent as discussedbelow, the composition subject to inkjet printing will in a preferredembodiment have certain characteristics, which makes it compatible forprinting, such as inkjet printing.

The composition can also be referred to as the print medium. Thecomposition may in one embodiment comprise a solvent and at least oneagent or bioactive agent.

The solvent or fluid component of the composition may be an aqueousmedium. The aqueous medium may contain salts, such as sodium chloride,dissolved therein, and thus the aqueous medium may be saline.

In another embodiment, the solvent or fluid component of the compositionis a volatile fluid. A volatile liquid is a liquid with a high vaporpressure or low boiling point. In other words, a volatile liquid mayevaporate at room temperature or vaporize easily.

In one embodiment, a water content stabilizer such as sorbitol,polysaccharides or polyols may be added to the composition.

Viscosity

The viscosity of a liquid may be increased by adding a substance thatincreases the viscosity of the liquid. Such substances may be long chainmolecules (polymers) that are soluble in that liquid; and gelatin,starch, polyethlyleneoxide, polyvinylalcohol and polyethyleneglycols(macrogol) are examples hereof

In another embodiment, a substance that increases the viscosity of theliquid may be added to the composition, selected from the non-limitinglist of acacia, alginic acid, bentonite, carbomer,carboxymethylcellulose calcium, carboxymethylcellulose sodium,cetostearyl alcohol, colloidal silicon dioxide, guar gum, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phtalate, magnesium aluminium silicate,methylcellulose, microcrystalline cellulose, polyvinyl alcohol,povidone, sodium alginate, sucrose, tragacanth, gelatin, starch,albumin, casein, polyethlyleneoxide, polyvinylalcohol,polyethyleneglycols (macrogol), glycerine (1,2,3-propanetriol) andglycol (1,2-propanediol).

The viscosity of the composition to be printed onto the surface of thematrix must be compatible with the print technology, and therefore musthave its viscosity within a specific range.

Viscosity is a measure of the resistance of a fluid to being deformed byeither shear stress or extensional stress. It is commonly perceived as“thickness”, or resistance to flow. Viscosity describes a fluid'sinternal resistance to flow and may be thought of as a measure of fluidfriction. Thus, water is “thin”, having a lower viscosity, whilevegetable oil is “thick” having a higher viscosity. All real fluids(except superfluids) have some resistance to stress, but a fluid whichhas no resistance to shear stress is known as an ideal fluid or inviscidfluid.

The SI physical unit of dynamic viscosity is the pascal-second (Pa·s),which is identical to 1 kg·m⁻¹·s⁻¹. If a fluid with a viscosity of onePas is placed between two plates, and one plate is pushed sideways witha shear stress of one pascal, it moves a distance equal to the thicknessof the layer between the plates in one second.

The cgs physical unit for dynamic viscosity is the poise (P), namedafter Jean Louis Marie Poiseuille. It is more commonly expressed,particularly in ASTM standards, as centipoise (cps). The centipoise iscommonly used because water has a viscosity of 1.0020 cps (at 20° C.;the closeness to one is a convenient coincidence). The relation betweenpoise and pascal-seconds is:

-   -   1 P=1 g·cm⁻¹·s⁻¹    -   10 P=1 kg·m⁻¹·s⁻¹=1 Pa·s    -   1 cps=0.001 Pa·s=1 mPa·s        In one embodiment of the invention, the viscosity of the        composition to be deposited or printed onto the surface of the        matrix is more than 1 cps, such as more than 5 cps, for example        more than 10 cps, such as more than 20 cps, for example more        than 30 cps, such as more than 40 cps, for example more than 50        cps, such as more than 60 cps, for example more than 70 cps,        such as more than 80 cps, for example more than 90 cps, such as        more than 100 cps, for example more than 150 cps, such as more        than 200 cps, for example more than 250 cps, such as more than        300 cps, for example more than 350 cps, such as more than 400        cps, for example more than 500 cps, such as more than 550 cps,        for example more than 600 cps, such as more than 650 cps, for        example more than 700 cps, such as more than 750 cps, for        example more than 800 cps, such as more than 850 cps, for        example more than 900 cps, such as more than 950 cps, for        example more than 1000 cps, such as more than 1100 cps, for        example more than 1200 cps, such as more than 1300 cps, for        example more than 1400 cps, such as more than 1500 cps, for        example more than 1600 cps, such as more than 1700 cps, for        example more than 1800 cps, such as more than 1900 cps, for        example more than 2000 cps, such as more than 2250 cps, for        example more than 2500 cps, such as more than 2750 cps, for        example more than 3000 cps.

In another embodiment of the invention, the viscosity of the compositionto be deposited or printed onto the surface of the matrix is in therange 1-5 cps, such as 5-10 cps, for example 10-15 cps, such as 15-20cps, for example 20-30 cps, such as 30-40 cps, for example 40-50 cps,such as 50-60 cps, for example 60-70 cps, such as 70-80 cps, for example80-90 cps, such as 90-100 cps, for example 100-150 cps, such as 150-200cps, for example 200-250 cps, such as 250-300 cps, for example 300-350cps, such as 350-400 cps, for example 400-450 cps, such as 450-500 cps,for example 500-550 cps, such as 550-600 cps, for example 600-650 cps,such as 700-750 cps, for example 750-800 cps, such as 800-850 cps, forexample 850-900 cps, such as 900-950 cps, for example 950-1000 cps, suchas 1000-1100 cps, for example 1100-1200 cps, such as 1200-1300 cps, forexample 1300-1400 cps, such as 1400-1500 cps, for example 1500-1600 cps,such as 1600-1700 cps, for example 1700-1800 cps, such as 1800-1900 cps,for example 1900-2000 cps, such as 2000-2250 cps, for example 2250-2500cps, such as 2500-2750 cps, for example 2750-3000 cps.

In a preferred embodiment of the invention, the viscosity of thecomposition is in the range of 0.1-20 cps; for example 0.1-1 cps, suchas 1-2 cps, for example 2-3 cps, such as 3-4 cps, for example 4-5 cps,such as 5-6 cps, for example 6-7 cps, such as 7-8 cps, for example 8-9cps, such as 9-10 cps, for example 10-11 cps, such as 11-12 cps, forexample 12-13 cps, such as 13-14 cps, for example 14-15 cps, such as15-16 cps, for example 16-17 cps, such as 17-18 cps, for example 18-19cps, such as 19-20 cps.

Surface Tension

Surface tension is an attractive property of the surface of a liquid. Itis what causes the surface portion of liquid to be attracted to anothersurface, such as that of another portion of liquid. Applying Newtonianphysics to the forces that arise due to surface tension accuratelypredicts many liquid behaviors that are so commonplace that most peopletake them for granted. Applying thermodynamics to those same forcesfurther predicts other more subtle liquid behaviors. Surface tension hasthe dimension of force per unit length (N/m or Newton per meter), or ofenergy per unit area (dyn/cm² or dyne per square centimeter).

In physics, dyne (meaning power, force) is a unit of force specified inthe centimetre-gram-second (CGS) system of units, a predecessor of themodern SI. One dyne is equal to exactly 10 micronewtons. Equivalently,the dyne is defined as “the force required to accelerate a mass of onegram at a rate of one centimetre per second squared”: 1 dyn=1g·cm/s²=10⁻⁵ kg·m/s²=10 μN

In a preferred embodiment of the invention, the surface tension of thecomposition is in the range of 0.020 to 0.050 N/m; for example0.020-0.022 N/m, such as 0.022-0.024 N/m, for example 0.024-0.026 N/m,such as 0.026-0.028 N/m, for example 0.028-0.030 N/m, such as0.030-0.032 N/m, for example 0.032-0.034 N/m, such as 0.034-0.036 N/m,for example 0.036-0.038 N/m, such as 0.038-0.040 N/m, for example0.040-0.042 N/m, such as 0.042-0.044 N/m, for example 0.044-0.046 N/m,such as 0.046-0.048 N/m, for example 0.048-0.050 N/m.

pH

pH is a measure of the acidity or alkalinity of a solution. Aqueoussolutions at 25° C. with a pH less than seven are considered acidic,while those with a pH greater than seven are considered basic(alkaline). When a pH level is 7.0, it is defined as ‘neutral’ at 25° C.because at this pH the concentration of H₃O⁺ equals the concentration ofOH⁻ in pure water. The normal pH of blood is in the range of 7.35-7.45.pH is formally dependent upon the activity of hydronium ions (H₃O⁺);pH=−log₁₀(aH⁺).

The pH of the compositions employed in the invention may be adjusted bythe addition of organic or inorganic acids or bases. Useful compositionsmay have a preferred pH of from about 2 to 10, depending upon the typeof composition being used. Typical inorganic acids include hydrochloric,phosphoric, and sulfuric acids. Typical organic acids includemethanesulfonic, acetic, and lactic acids. Typical inorganic basesinclude alkali metal hydroxides and carbonates. Typical organic basesinclude ammonia, triethanolamine and tetramethylethlenediamine.

Formulation of the Bioactive Agent of the Composition

The composition printed onto the surface of a matrix material may befurther adapted to comprise controlled release formulation,incorporation into microspheres and/or aerogels or the like.

Controlled Release

Time release technology, also known as Sustained-release (SR),extended-release (ER, XR, or XL), time-release or timed-release,controlled-release (CR), or continuous-release (CR); refers to acomposition formulated to dissolve slowly and release a drug or agentover time. The advantages of sustained-release compositions are thatthey can often be used less frequently than instant-release formulationsof the same drug or agent, and that they keep steadier levels of thedrug in the bloodstream. Sustained-release compositions are formulatedso that the active ingredient is embedded in a matrix of insolublesubstance so that the dissolving drug or agent has to find its way outthrough the holes in the matrix. In some CR formulations the matrixphysically swells up to form a gel, so that the drug has first todissolve in matrix, then exit through the outer surface.

In one embodiment, the composition according to the present invention isa controlled release composition, wherein the bioactive agent(s) of thecomposition is released from said composition in a prolonged manner. Thebioactive agent may be released from the composition printed onto thesurface of a matrix during a period of between 1 minute to 14 days; suchas 1 to 5 minutes, for example 5 to 15 minutes, such as 15 to 30minutes, for example 30 to 45 minutes, such as 45 to 60 minutes, forexample 60 to 75 minutes, such as 75 to 90 minutes, for example 90 to120 minutes, such as 120 to 150 minutes, for example 150 to 180 minutes,such as 180 to 210 minutes, for example 210 to 240 minutes, such as 4hours to 5 hours, for example 5 to 6 hours, such as 6 to 7 hours, forexample 7 to 8 hours, such as 8 to 9 hours, for example 9 to 10 hours,such as 10 to 11 hours, for example 11 to 12 hours, such as 12 to 13hours, for example 13 to 14 hours, such as 14 to 15 hours, for example15 to 16 hours, such as 16 to 17 hours, for example 17 to 18 hours, suchas 18 to 19 hours, for example 19 to 20 hours, such as 20 to 21 hours,for example 21 to 22 hours, such as 22 to 23 hours, for example 23 to 24hours, such as 24 to 30 hours, for example 30 to 36 hours, such as 36 to42 hours, for example 42 to 48 hours, such as 48 to 54 hours, forexample 54 to 60 hours, such as 60 to 66 hours, for example 66 to 72hours, such as 3 days to 3.5 days, for example 3.5 to 4 days, such as 4to 4.5 days, for example 4.5 to 5 days, such as 5 to 5.5 days, forexample 5.5 to 6 days, such as 6 to 6.5 days, for example 6.5 to 7 days,such as 7 to 8 days, for example 8 to 9 days, such as 8 to 10 days, forexample 10 to 11 days, such as 11 to 12 days, for example 12 to 13 days,such as 13 to 14 days.

The controlled release formulation may be any controlled releaseformulation known to the skilled person, such as those disclosed in WO99/051208, WO 04/084869, WO 06/128471, WO 03/024429, WO 05/107713 and WO03/024426 (Egalet as Applicant).

Aerogels

An aerogel is a low-density solid-state material derived from gel inwhich the liquid component of the gel has been replaced with gas. Theresult is an extremely low-density solid with several remarkableproperties, most notably its effectiveness as a thermal insulator.Aerogels are produced by extracting the liquid component of a gelthrough supercritical drying. This allows the liquid to be slowly drawnoff without causing the solid matrix in the gel to collapse fromcapillary action, as would happen with conventional evaporation.Aerogels may be produced from silica gels (Silaca aerosols), alumina(Alumina aerogels), chromia, tin oxide, agar (SEAgel), sulfur,chalcogens (Chalcogel), metals, cadmium selenide and carbon (Carbonaerogels).

In one embodiment, the composition according to the present invention iscapable of forming an aerogel, wherein the bioactive agent(s) of thecomposition is retained or encapsulated in the aerogel composition onthe surface of the matric material. The one or more encapsulatedbioactive agents can in one preferred embodiment be released from theaerogel over time. In one embodiment the encapsulated bioactive agentscomprises enzymes.

Microsperes

Microspheres are spherical particles composed of various natural andsynthetic materials with diameters in the micrometer range

In one embodiment, the composition comprising bioactive agent(s)according to the present invention is retained or encapsulated inmicrospheres on the surface of the matric material. The one or moreencapsulated bioactive agents can in one preferred embodiment bereleased from the microsphere over time.

In one embodiment, the microspheres are biodegradable. Biodegradation isthe process by which organic substances are broken down by the enzymesproduced by living organisms.

Matrix Comprising Thrombin

In another embodiment the present invention relates to a kit-of-partscomprising a matrix comprising thrombin. The matrix comprising thrombinmay also comprise further thrombin-stabilizing agents.

The matrix comprising thrombin comprises in one embodiment one or moreof the compositions listed herein below:

-   -   A matrix according to the present invention wherein thrombin        and/or any other pharmaceutically active compound is printed        onto said matrix    -   Thrombi-Gel, Thrombi-Pad or ThrombiGel hemostatic foam (Vascular        Solutions, Inc.)    -   D-Stat Dry product (D-Stat Dry, D-Stat 2 Dry) (Vascular        Solutions, Inc.)    -   a gelatin foam pad and/or a gauze pad that provide a unique,        premixed, sterile, gelatin/thrombin haemostat    -   a premixed thrombin/gelatin pad    -   thrombin freeze-dried into a gelatin foam any standard gelatin        pad with thrombin    -   A hemostatic paste composition comprising a hemostatic effective        amount of thrombin in a polyethylene glycol base which is        preferably prepared by admixing an aqueous solution of thrombin        and polyethylene glycol and freeze-drying the mixture to remove        substantially all of the water to yield a viscous water soluble        paste of fine particles of thrombin uniformly dispersed        throughout the polyethylene glycol base (as described in U.S.        Pat. No. 5,595,735)    -   collagen paste hemostats comprising thrombin e.g. as described        in U.S. Pat. No. 4,891,359    -   a stable collagen sponge having thrombin therein e.g. as        described in U.S. Pat. No. 4,515,637.    -   a collagen sponge having thrombin therein e.g. as described in        U.S. Pat. No. 6,649,162    -   FloSeal Matrix Hemostatic Sealant    -   Gelfoam comprising thrombin    -   Surgifoam comprising thrombin    -   Surgiflo comprising thrombin    -   Sponge comprising thrombin    -   biologically absorbable material comprising thrombin    -   Fibrinpaste based on e.g. a collagen sponge coated with        fibrinogen and/or thrombin    -   TachoSil (Nycomed)    -   a collagen material (such as Avitene, Actifoam, Helistat,        Inistat) comprising thrombin    -   CoStasis hemostatic device    -   a cellulose material (such as Surgicel Oxycel or Tabotamp)        comprising thrombin

The thrombin may be any thrombin, such as Thrombostat, Thrombin-JMI(King Pharmaceuticals), Recothrom (Bayer/Zymogenetics), Evithrom (OMRIXBiopharmaceuticals/Ethicon), Evicel or any other commercially availablethrombin. Thrombin may also be produced from plasma using the ThrombinActivation Device (TAD)

(Thermogenesis) Hemostasis

The present invention is directed in one aspect to regulating orcontrolling or promoting hemostasis.

Coagulation is a complex process by which blood forms solid clots. It isan important part of hemostasis (the cessation of blood loss from adamaged vessel) whereby a damaged blood vessel wall is covered by aplatelet- and fibrin-containing clot to stop bleeding and begin repairof the damaged vessel. Disorders of coagulation can lead to an increasedrisk of bleeding and/or clotting and embolism.

Coagulation is highly conserved throughout biology; in all mammals,coagulation involves both a cellular (platelet) and a protein(coagulation factor) component. Coagulation is initiated almostinstantly after an injury to the blood vessel damages the endothelium(lining of the vessel). Platelets immediately form a hemostatic plug atthe site of injury; this is called primary hemostasis. Secondaryhemostasis occurs simultaneously—proteins in the blood plasma, calledcoagulation factors, respond in a complex cascade to form fibrin strandswhich strengthen the platelet plug. Later, as wound healing occurs, theplatelet aggregate and fibrin clot are broken down.

Damage to blood vessel walls exposes collagen normally present under theendothelium. Circulating platelets bind to the collagen with the surfacecollagen-specific glycoprotein Ia/IIa receptor. This adhesion isstrengthened further by the large multimeric circulating protein vonWillebrand factor (vWF), which forms links between the plateletglycoprotein Ib/IX/V and collagen fibrils.

The platelets are then activated and release the contents of theirgranules into the plasma, in turn activating other platelets. Theplatelets undergo a change in their shape which exposes a phospholipidsurface for those coagulation factors that require it. Fibrinogen linksadjacent platelets by forming links via the glycoprotein IIb/IIIa. Inaddition, thrombin activates platelets.

The coagulation cascade of secondary hemostasis has two pathways, thecontact activation pathway (formerly known as the intrinsic pathway) andthe tissue factor pathway (formerly known as the extrinsic pathway) thatlead to fibrin formation. It was previously thought that the coagulationcascade consisted of two pathways of equal importance joined to a commonpathway. It is now known that the primary pathway for the initiation ofblood coagulation is the tissue factor pathway. The pathways are aseries of reactions, in which a zymogen (inactive enzyme precursor) of aserine protease and its glycoprotein co-factor are activated to becomeactive components that then catalyze the next reaction in the cascade,ultimately resulting in cross-linked fibrin. Coagulation factors aregenerally indicated by Roman numerals, with a lowercase a appended toindicate an active form.

The coagulation factors are generally serine proteases (enzymes). Thereare some exceptions. For example, FVIII and FV are glycoproteins andFactor XIII is a transglutaminase. Serine proteases act by cleavingother proteins at specific sites. The coagulation factors circulate asinactive zymogens.

The coagulation cascade is classically divided into three pathways. Thetissue factor and contact activation pathways both activate the “finalcommon pathway” of factor X, thrombin and fibrin.

The main role of the tissue factor pathway is to generate a “thrombinburst”, a process by which thrombin, the most important constituent ofthe coagulation cascade in terms of its feedback activation roles, isreleased instantaneously. FVIIa circulates in a higher amount than anyother activated coagulation factor.

Following damage to the blood vessel, endothelium Tissue Factor (TF) isreleased, forming a complex with FVII and in so doing, activating it(TF-FVIIa). TF-FVIIa then activates FIX and FX. FVII is itself activatedby thrombin, FXIa, plasmin, FXII and FXa. The activation of FXa byTF-FVIIa is almost immediately inhibited by tissue factor pathwayinhibitor (TFPI). FXa and its co-factor FVa form the prothrombinasecomplex which activates prothrombin to thrombin. Thrombin then activatesother components of the coagulation cascade, including FV and FVII(which activates FXI, which in turn activates FIX), and activates andreleases FVIII from being bound to vWF. FVIIIa is the co-factor of FIXaand together they form the tenase complex which activates FX and so thecycle continues.

In one embodiment of the present invention, thrombin may be a bioactiveagent comprised in the pharmaceutical composition of the presentinvention.

The contact activation pathway begins with formation of the primarycomplex on collagen by high-molecular weight kininogen (HMWK),prekallikrein, and FXII (Hageman factor). Prekallikrein is converted tokallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. FactorXIa activates FIX, which with its co-factor FVIIIa form the tenasecomplex, which activates FX to FXa. The minor role that the contactactivation pathway has in initiating clot formation can be illustratedby the fact that patients with severe deficiencies of FXII, HMWK, andprekallikrein do not have a bleeding disorder.

The final common pathway. Thrombin has a large array of functions. Itsprimary role is the conversion of fibrinogen to fibrin, the buildingblock of a hemostatic plug. In addition, it activates Factors VIII and Vand their inhibitor protein C (in the presence of thrombomodulin), andit activates Factor XIII (denoted XIIIa in its activated form), whichforms covalent bonds that crosslink the fibrin polymers that form fromactivated monomers. Following activation by the contact factor or tissuefactor pathways the coagulation cascade is maintained in a prothromboticstate by the continued activation of FVIII and FIX to form the tenasecomplex, until it is down-regulated by the anticoagulant pathways.

In one embodiment of the present invention, thrombin may be a bioactiveagent comprised in the pharmaceutical composition of the presentinvention. In a further embodiment, fibrinogen may be a bioactive agentcomprised in the pharmaceutical composition of the present invention. Inyet a further embodiment, Factor XIII and/or XIIIa may be a bioactiveagent comprised in the pharmaceutical composition of the presentinvention.

Three mechanisms keep the coagulation cascade in check. Abnormalitiescan lead to an increased tendency toward thrombosis. 1) Protein C is amajor physiological anticoagulant. It is a vitamin K-dependent serineprotease enzyme that is activated by thrombin into activated protein C(APC). The activated form (with protein S and phospholipid as acofactor) degrades Factor Va and Factor VIIIa. Quantitative orqualitative deficiency of either may lead to thrombophilia (a tendencyto develop thrombosis). Impaired action of Protein C (activated ProteinC resistance), for example by having the “Leiden” variant of Factor V orhigh levels of Factor VIII also may lead to a thrombotic tendency. 2)Antithrombin is a serine protease inhibitor (serpin) that degrades theserine proteases; thrombin and FXa, as well as Factor XIIa, and FactorIXa. It is constantly active, but its adhesion to these factors isincreased by the presence of heparan sulfate (a glycosaminoglycan) orthe administration of heparins (different heparinoids increase affinityto Factor Xa, thrombin, or both). Quantitative or qualitative deficiencyof antithrombin (inborn or acquired, e.g. in proteinuria) leads tothrombophilia. 3) Tissue factor pathway inhibitor (TFPI) inhibits FactorVIIa-related activation of Factor IX and Factor X after its originalinitiation.

Various substances are required for the proper functioning of thecoagulation cascade. Calcium and phospholipid (a platelet membraneconstituent) are required for the tenase and prothrombinase complexes tofunction. Calcium mediates the binding of the complexes via the terminalgamma-carboxy residues on Factor Xa and Factor IXa to the phospholipidsurfaces expressed by platelets as well as procoagulant microparticlesor microvesicles shedded from them. Calcium is also required at otherpoints in the coagulation cascade. Vitamin K is an essential factor to ahepatic gamma-glutamyl carboxylase that adds a carboxyl group toglutamic acid residues on Factors II, VII, IX and X, as well as ProteinS, Protein C and Protein Z. Deficiency of vitamin K (e.g. inmalabsorption), use of inhibiting anticoagulants (warfarin,acenocoumarol and phenprocoumon) or disease (hepatocellular carcinoma)impairs the function of the enzyme and leads to the formation of PIVKAs(proteins formed in vitamin K absence) this causes partial or non gammacarboxylation and affects the coagulation factors ability to bind toexpressed phospholipid.

Wound Healing

The present invention is directed in one aspect to regulating orcontrolling or promoting wound healing.

The outer layer of skin surrounding the body performs an importantprotective function as a barrier against infection, and serves as ameans of regulating the exchange of heat, fluid and gas between the bodyand external environment.

Wounds to the skin and the underlying tissues of animals may be causedby e.g. friction, abrasion, laceration, burning or chemical irritation.Tissue damage may also result from internal metabolic or physicaldysfunction, including, but not limited to, bone protrudence, diabetes,circulatory insufficiencies, or inflammatory processes.

A wound to the skin and/or damage to the underlying tissuessignificantly reduce the protective function of the skin. Consequently,damaged skin results in an increased risk of infection of the underlyingtissue by infectious agents such as bacteria and vira.

Areas of damaged skin are conventionally protected by the application ofa wound or tissue dressing which facilitates wound healing. Wound ortissue dressings generally provide a suitable environment for woundhealing, they absorb drainage, immobilize the wound, promote hemostasisand protect the wound and new tissue growth from bacterialcontamination.

The healing of wounds or related forms of tissue damage generallydepends on cellular proliferation and the formation of new connective,endothelial, and epithelial tissue as explained briefly herein below.

Several agents have been reported to favorably influence the cellularprocesses involved in wound healing, e.g., polypeptid growth factors,allantoin, Vitamin A (and derivatives), zinc, exogenous DNA, and aloevera preparations. These compounds operate through various poorlydefined mechanisms and display varying degrees of effectiveness inparticular applications

When an injury occurs, cell damage comes from the precipitating event,such as a cut, resulting in ruptured cells and severed or crushedcapillaries and other blood vessels. The interruption of blood flowproduces anoxia, causing the death of additional cells. Within 15minutes of injury the wound is filled with dead and dying cells,extracellular substances collagen, elastic fibers, fat and groundsubstances, extravasated blood, and possibly bacteria and virusesintroduced by the injurious agent. Tissue damage is not restricted tothe initial area of injury; it may increase over the next several hoursor days as a result of the release of lysomal enzymes from the injuredcells or as a consequence of swelling and infection. (See Reese et al.,Role of Fibronectin in Wound Healing, the subject matter of which ishereby incorporated by reference).

Coagulation, the first phase of the healing process, bridges the gapbetween the injury and the inflammatory response, the second phase ofwound healing. It stops the loss of blood and restores some of themechanical and physical integrity to the damaged tissue. The coagulationcascade is described in detail elsewhere herein.

The second phase of wound repair is the inflammatory response, which isnecessary for subsequent phases of healing. It is initiated by therelease of histamine and serotonin from platelets and mast cells and bykinins. Histamine and kinins act to increase capillary dilation, openingpreviously closed capillaries in the area of injury. The increased bloodflow through the capillary beds produces two of the characteristics ofthe inflammatory response: redness and heat. Prostaglandin releasewithin a few hours of injury results in the full development of theinflammatory response, which may last from 3 to 5 days depending on theextent of the injury. The extreme vasodilation produced by the factorsjust discussed causes a widening of the endothelial cell junctionslining the capillaries. Fluid and macromolecular components of bloodescape into the tissues through the gaps, producing swelling, the thirdcharacteristic of the inflammatory response. If the swelling isextensive, it may interrupt blood flow, increasing the extent of injuryas a result of anoxia. Pain, the final characteristic of inflammation,results from a combination of the kinins as well as the direct effect oflysosomal enzymes and pressure from the swelling on nerve endings.

Control of infection at the wound site is of critical importance insuccessful wound repair. Infections delay healing, enlarge the woundlesion, may lead to systemic infection, and greatly increase thelikelihood of disfiguring and physically debilitating scars.Vasodilation of the capillary beds reduces the velocity of blood throughthe capillaries. This, along with the production of potent chemotacticfactors from the complement fixation and the release of chemotacticagents from the damaged tissue, cause the accumulation ofpolymorphonuclear leukocytes (“PMN's”) along the walls of thecapillaries which are the host's major cellular defense againstinfection. The PMNs subsequently pass through the endothelial junctionsof the capillary wall into the site of the injury. If bacteria arepresent in the wound, they may release soluble chemotactic factorsand/or activate complement with the subsequent generation of chemotacticfragments. PMN's at the site of an infection or injury release substancethat affect the PMNs' mobility, keeping them at the site. Fibronectinfacilitates the attachment of the bacterium to the membrane of thephagocyte.

Dead cells, cellular debris, and extracellular proteins must then beremoved or readsorbed to allow revascularization and repair to continue.Macrophages are primarily responsible for the clearance of wound debris.Wound macrophages, like wound PMN's, are actively phagocytic. Theymigrate into the wound using the fibers of the fibrin clot as a scaffoldto move within the clot, attaching to the fibers through fibronectin.The macrophages encounter, engulf, and destroy the dead cells trapped inthe clot matrix, as well as the damaged cells from the wound margin. Thefibrin clot itself is resolved primarily by the activation of theplasminogen that was incorporated into the fibers during theirformation. Some of the fibrin fragments are engulfed by macrophages inthe area. Since most of the clot fragments are released away from thearea of the most intense macrophage activity, many of the fragments areremoved by lymphatic drainage and thus enter the circulation. Thesesoluble complexes are removed by the sessile cells of the RES, primarilythose of the spleen and liver. Also, PMN's trapped in the clot die as aresult of anoxia, releasing their lysosomal contents. These enzymesattack the surrounding clot and dissolve it. Although the release oflysosomal enzymes by PMN's may be considered beneficial to the host inmost cases, they may also increase tissue destruction and delay healing.If the PMN's accumulate rapidly within the wound and remain there (as inan infection), their lysosomal enzymes dissolve significant portions ofthe clot, removing the framework used by the macrophages and fibroblaststo move into the wound and re-colonize it. These areas of destructionmust eventually be drained or slowly removed by the macrophages. Thedissolved portion of the clot is then replaced as part of the chronicinflammatory response.

Repair, or fibroplasia, of the damaged tissue occurs during some of theabove stages. Within 12 to 24 hours of injury, fibroblasts, includingthose at some distance from the wound margins, begin to move toward thearea of injury and to proliferate. This response is apparently due tofactors released by the injured tissue and platelets and possibly tofactors released by the kinin, complement or coagulation cascades. Theproliferating fibroblasts derive part of their nutrients from thecomponents of tissue debris and cells released by macrophages. Thefibroblast phase may last 2 to 4 weeks in a skin wound, whereas it maypersist several months in an injury to the stomach or intestines.Fibroblasts, as the macrophages did, use the fibers of the fibrin clotas a scaffold to move into and within the damages area. The Fibroblastssynthesize and secrete sufficient quantities of fibronectin to promotetheir own attachment to fibronectin deficient substrates.

Angiogenesis, or revascularization, begins with the growth of capillarybeds into the area directly behind the fibroblasts. In the early phasesof wound repair, the capillaries are much more numerous than in normaltissue, which probably reflects the high oxygen and nutrientrequirements of the rapidly regenerating tissue. The capillaries arevery leaky, which facilitates the movement of cells and macromoleculesinto the wound site. Eventually, the capillaries originating from oneside of the wound grow into contact with capillaries originating fromthe other sides and fuse, reestablishing complete circulation within thewound.

By the end of the fifth day after the injury, fibroblasts begin layingdown large quantities of collagen. The collagen molecule is synthesizedon the membrane of the endoplastic reticulum. It then undergoesextensive postranslational modification, hydroxylation, glycosylation,and further steps to form the procollagen molecule. The procollagenmolecule is then secreted and is further modified to tropocollagen byspecific serum peptidases. These activated tropocollagen moleculesquickly polymerize to form increasingly large collagen fibers.Thereafter, crosslinking among the collagen fibers occurs. The collagennetwork in effect replaces the fibrin clot as the major structuralelement of the wound. This becomes particularly important during theremodeling phase of wound healing.

Reepithelialization begins to occur within a few hours of injury as theattachment of the epithelial cells to the dermis loosened near themargin of the wound, and the cells begin to migrate over the defect,always maintaining contact with the mesenchymal tissue. By 48 hoursafter the injury, the cells are also beginning to proliferate to replacethe lost cells. The epithelial cells continue to divide after the bridgeis complete to form a thicker epithelium. Wound contracture aidsreepithelialization insofar as it reduces the size of the defect to bereepithelialized by as much as 50%. Contracture is believed to occur asa result of the cellular element of the granulation tissue in thewound—the fibroblasts and myofibroblasts.

Remodeling is the last step of wound healing. Scar tissue continues togain tensile strength for several months after collagen contentstabilizes. This gain in strength comes from the rearrangement of thecollagen in the wound and perhaps from increased crosslinking of thecollagen. Collagen accumulation is the sum of synthesis and destruction,and both occur simultaneously during the wound healing process. Afterabout 14 days, a balance between collagen synthesis and degradation isreached. The collagenase involved in the remodeling comes fromepithelial cells, from fibroblasts encountering new epithelium, and frommacrophages that contain collagenase in their lysosomes.

Typical wound healing takes anywhere from 5 to 21 days. This time periodis of course longer for the immune compromised patient because suchpatients are frequently unable to sufficiently stabilize the wound andward off infection which prevents the proper adherence of fibrin,fibronectin or collagen at an acceptable rate at the locus of the wound.For example, those with vasculitis or other rheumatic or diabeticdiseases frequently experience wound healing times far in excess ofseveral weeks. Diabetics frequently develop lesions that take weeks toheal.

Others, such as those with artificial limbs, have continuous injuries atthe point of contact between the limb and the point of attachment to thebody. Burns also present healing problems insofar as the burned tissueis incapable of timely production of fibrin. Accordingly, there is agreat need to shorten the duration of time necessary for wound or burnhealing to occur.

Wound or Tissue Dressings

When referring to a wound or tissue dressing, it is understood that saidwound or tissue dressings may be imprinted with the fluid or liquidcomposition according to the present invention primarily in the wound ortissue contacting area of said wound or tissue dressing.

Types of Wound and Tissue Dressings

“Wound” refers broadly to injuries to the skin and underlying(subcutaneous) tissue initiated in different ways (e.g., pressure soresfrom extended bed rest and wounds induced by trauma) and with varyingcharacteristics. Wounds may be classified into one of four gradesdepending on the depth of the wound: i) Grade I: wounds limited to theepithelium; ii) Grade II: wounds extending into the dermis; iii) GradeIII: wounds extending into the subcutaneous tissue; and iv) Grade IV (orfull-thickness wounds): wounds wherein bones are exposed (e.g., a bonypressure point such as the greater trochanter or the sacrum). Thepresent invention relates to treatment of any type of wound mentionedabove using one or more types of wound and/or tissue dressings asdescribed below.

Several types of wound or tissue dressings exist. Most wound or tissuedressings are designed to maintain a moist wound bed. The most commonlyused wound or tissue dressing are briefly introduced below. The presentinvention relates one or more types of wound and/or tissue dressingsincluded the ones mentioned below printed with one or morepharmaceutical compositions.

Synthetic wound dressings originally consisted of two types; gauze-baseddressings and paste bandages such as zinc paste bandages. In themid-1980s the first modern wound dressings were introduced whichdelivered important characteristics of an ideal wound dressing: moisturekeeping and absorbing (e.g. polyurethane foams, hydrocolloids) andmoisture keeping and antibacterial (e.g. iodine-containing gels).

During the mid 1990s, synthetic wound dressings expanded into e.g. thefollowing groups of products: 1) vapor-permeable adhesive films, 2)hydrogels, 3) hydrocolloids, 4) alginates, 5) synthetic foam dressings,6) silicone meshes, 7) tissue adhesives, 8) barrier films and 9) silver-or collagen-containing dressings.

Synthetic wound dressings can be broadly categorized into the followingtypes as indicated in the table below.

TABLE 6 Type Properties Passive Traditional dressings that provide coverover the products wound, e.g. gauze and tulle dressings InteractivePolymeric films and forms which are mostly products transparent,permeable to water vapour and oxygen, non-permeable to bacteria, e.g.hyaluronic acid, hydrogels, foam dressings Bioactive Dressings whichdeliver substances active in wound products healing, e.g. hydrocolloids,alginates, collagens, chitosan

Alginate dressings are highly absorbent, biodegradable dressings derivedfrom seaweed. They are used for wounds with moderate to large amounts ofexudate, and for wounds requiring packing. These dressings work bycombining with the wound exudate to form a hydrophilic gel that createsa moist healing environment.

Hydrocolloid dressings are among the oldest and most frequently usedwound or tissue dressings. They are indicated for partial thicknesswounds, Stage III, granulating Stage IV pressure ulcers, and can be usedin the treatment of venous stasis ulcers. Hydrocolloid dressings areeither occlusive (i.e. they do not allow air to escape through thedressing), or semi-occlusive (i.e. they do allow some air to escapethrough the dressing) and they are designed to seal the wound bed toretain and interact with exudate to promote healing. While absorbingexudate, the hydrocolloid dressing forms a gel.

Hydrogel dressings are either sheets of cross-linked polymers orhydrogel impregnated gauze, or non-wowen sponge, used to cover a wound.The hydrogel dressing can be in the form of a hydrogel sheet dressing orin the form of an amorphous hydrogel dressing. Hydrogel sheet dressingsare indicated for partial and full thickness wounds, wounds withnecrosis or slough, and burns. An amorphous hydrogel dressing is a soft,formless gel comprised of either polymers or copolymers and up to 95percent water, whereas a hydrogel sheet dressing is a firm sheet.Amorphous hydrogels carry the same indications as hydrogel sheets andthey can also be used to lightly pack full-thickness wounds.

Foam dressings are semipermeable sheets of a polymer, such aspolyurethane, that provide a specific, controlled moisture andtemperature environment for wound healing. They are indicated forfull-thickness wounds with moderate to heavy exudate. Foam dressings arenon-adherent and can repel contaminants.

Transparent film dressings are made of e.g. polyurethane, polyamide orgelatin. Although they are waterproof, transparent film dressings aresomewhat porous allowing for oxygen and moisture to cross through theirbarriers. They are non-absorptive so they must be changed often forwounds with exudate. They are generally effective on dry wounds withnecrotic tissue in need of autolytic debridement. Transparent filmdressings are also used as a secondary material to secure e.g.non-adhesive gauzes and other types of dry dressings.

Composite dressings combine physically distinct components into a singledressing, and provide bacterial protection, absorption, and adhesion.

Gauze dressings are available in a number of forms including sponges,pads, ropes, strips, and rolls, gauze can also be impregnated withpetroleum, antimicrobials, and saline. With removal of a dried dressing,there is a risk of wound damage to the healing skin surrounding thewound.

The following table describes some of the many different types of wounddressings and their main properties:

TABLE 7 Type Properties Gauze Dressings can stick to the wound surfaceand disrupt the wound bed when removed. Only use on minor wounds or assecondary dressings Tulle Dressing does not stick to wound surface.Suitable for flat, shallow wound. Useful in patient with sensitive skin.E.g. Jelonet ®, Paranet ® Semipermeable film Sterile sheet ofpolyurethane coated with acrylic adhesive. Transparent allowing woundchecks. Suitable for shallow wound with low exudate. E.g. OpSite ®,Tegaderm ® Hydrocolloids Composed of carboxymethylcellulose, gelatin,pectin, elastomers and adhesives that turn into a gel when exudate isabsorbed. This creates a warm, moist environment that promotesdebridement and healing. Depending on the hydrocolloid dressing chosencan be used in wounds with light to heavy exudate, sloughing orgranulating wounds. Available in many forms (adhesive or non-adhesivepad, paste, powder) but most commonly as self-adhesive pads. E.g.DuoDERM ®, Tegasorb ® Hydrogels Composed mainly of water in a complexnetwork or fibres that keep the polymer gel intact. Water is released tokeep the wound moist. Used for necrotic or sloughy wound beds torehydrate and remove dead tissue. Do not use for moderate to heavilyexudating wounds. E.g. Tegagel ®, Intrasite ® Alginates Composed ofcalcium alginate (a seaweed component). When in contact with wound,calcium in the dressing is exchanged with sodium from wound fluid andthis turns dressing into a gel that maintains a moist wound environment.Good for exudating wounds and helps in debridement of sloughing wounds.Do not use on low exudating wounds as this will cause dryness andscabbing. Dressing should be changed daily. E.g. Kaltostat ®, Sorbsan ®Polyurethane or Designed to absorb large amounts of exudates. Maintain asilicone foams moist wound environment but are not as useful asalginates or hydrocolloids for debridement. Do not use on low exudatingwounds as this will cause dryness and scabbing. E.g. Allevyn ®,Lyofoam ® Hydrofibre Soft non-woven pad or ribbon dressing made fromsodium carboxymethylcellulose fibres. Interact with wound drainage toform a soft gel. Absorb exudate and provide a moist environment in adeep wound that needs packing. Collagens Dressings come in pads, gels orparticles. Promote the deposit of newly formed collagen in the woundbed. Absorb exudate and provide a moist environment

No single dressing is suitable for all types of wounds. Often a numberof different types of dressings will be used during the healing processof a single wound. The present invention relates in one embodiment todressings with one or more of the following functions: 1) Maintain amoist environment at the wound/dressing interface; 2) Absorb excessexudate without leakage to the surface of the dressing; 3) Providethermal insulation and mechanical protection; 4) Provide bacterialprotection; 5) Allow gaseous and fluid exchange; 6) Absorb wound odor;7) Be non-adherent to the wound and easily removed without trauma; 8)Provide some debridement action (remove dead tissue and/or foreignparticles); 9) Be non-toxic, non-allergenic and non-sensitizing (to bothpatient and medical staff); 10) Sterile.

Wound or Tissue Dressings Comprising an Absorbent Compound

In another aspect there is provided a wound or tissue dressingcomprising an absorbent compound for absorbing wound exudate, whereinsaid wound or tissue dressing has been printed with one or morepharmaceutical compositions. None limiting examples of absorbentcompound is given below.

The absorbent compound in one embodiment comprises or consists of ahydrogel forming material. The hydrogel forming material can form anamorphous hydrogel, but the hydrogel forming material can also be in theform of e.g. a sheet in which case the dressing will be a hydrogel sheetdressing.

In other embodiments, the absorbent compound of the wound or tissuedressing comprises or consists of a hydrocolloid forming material.

The absorbent compound can comprises or consist of a porous polymersuitable for entry of wound extrudate therein, i.e. the capillary forceallows wound extrudate to enter into the porous polymer. The porouspolymer is often hydrophilic or sufficiently hydrophilic to allowtransport of wound extrudate.

In a still further embodiment the absorbent compound comprises orconsists of a foam forming material.

It is important that the absorbent compound is in fluid contact with thewound e.g. through a gel or a matrix, such as a scaffold, or,alternatively, that the absorbent compound can contact the wounddirectly.

The bioabsorbable and/or porous material of the absorbent compound canbe adapted for serving as scaffold for new cells to attach andproliferate. Such a “connective” absorbent compound can remain in placeon the wound bed throughout the healing process, and later be absorbedand replaced by new tissue. During the wound healing process, theconnective absorbent compound will transmit wound exudate from the woundbed to the bioabsorbable and/or porous material of the absorbentcompound.

The absorbent compound can be a material that is absorbent to liquidwhile at the same time serves as a barrier for cell adhesion andpenetration by growing cells and larger proteins in wound exudate. Suchan absorbent compound can be referred to as an “absorbent barriermaterial”. An absorbent barrier material can e.g. prevent bacteriapresent in the bioabsorbable and/or porous material of the absorbentcompound from entering the wound itself. However, bioactive agentsproduced said bacteria and having wound healing promoting abilities areallowed to enter the wound area.

Besides absorbing wound exudate and inhibiting the loss of beneficialgrowth factors from the scaffold material, the absorbent compound canalso act as a reservoir for liquids to hydrate the wound. The featuresof non-adhesion and resistance to penetration by cells provide theimportant advantage that the absorbent barrier material—and anysubsequent connective compound—is easily removed and/or replaced asneeded without causing trauma to growing cells or tissue.

If desirable, the absorbent compound can be in contact with a furthercompound, such as a breathable film that can serve as a barrier to theentry of contaminants into the wound bed. One example of such a barrieris a topfilm. The absorbent compound can be any of the materials used inwound care. Materials that can be used as an absorbent compound includefabrics, foams or fibers of e.g. polyester, polypropylenes,polyethylenes and the which are optionally bonded to polyester film(such as Kendall's Novenette). Other suitable materials include, but arenot limited to, natural and synthetic polymeric absorbents,hydrocolloids, superabsorbents, and cellulosic absorbents. Cellulosicmaterials include cotton, rayon, wood and cellulose.

The superabsorbent compound may be in any suitable form. Typicalsuperabsorbents include starch grafted copolymers of acrylate salts,starch grafted copolymers of acrylamide salts, polyacrylate salts andthe like, including mixtures thereof.

Superabsorbent compounds and composites are easily prepared orcommercially available. Once such product is the composite air laidsuperabsorbent pad (dry forming process and the superabsorbent fiberflock SAFF) sold by Hanfspinnern Steen & Company. The superabsorbent mayalso be a delayed released web superabsorbent.

Superabsorbent webs that may be used in the present invention to serveas, or to be incorporated into, the absorbent compound can also includecarded or random webs made from, for example, cotton, rayon,polyethylene, polyester, or wool. Another suitable web is a spun-lacedweb made from polyester, polypropylene, or polyethylene. Thesuperabsorbent webs may also be in the form of tissues either single plyor multiple ply and either creped or uncreped. Delnet, a product ofApplied Extrusion Technologies which consists of a range of materialsmanufactured from polyethylene or polypropylene using extrusionembossing and orientation processes may also be used as a web forpreparing a superabsorbent web.

Superabsorbent webs can be formed by any convenient means, e.g., byslightly moistening or misting a web. After misting, a powderedsuperabsorbent may be applied followed by running the web through a dryoven or heating the roll. The powder adjacent to the moistened web willbecome tacky and adhere to the adjacent material (fibre, surface), andthe loose powder would then be vacuumed off.

Alternatively, superabsorbent powder can be sandwiched between non-wovenwebs/paper and subjected to moist steam which would make thesuperabsorbent tacky so that it would then stick to adjacent surfaces.The sandwiched superabsorbent and web would then be dried, creating atwo-ply web with superabsorbent between them. The superabsorbentconnective compound can also be heat bonded to the other connectivecompounds.

The wound or tissue dressing according to the present invention cancontain from about 5% to about 50% by weight of water, such as fromabout 5% to about 40% by weight of water, for example from about 5% toabout 30% by weight of water, such as from about 5% to about 25% byweight of water, for example from about 5% to about 20% by weight ofwater, such as from about 5% to about 15% by weight of water, forexample from about 5% to about 10% by weight of water, such as fromabout 10% to about 40% by weight of water, for example from about 10% toabout 30% by weight of water, such as from about 10% to about 25% byweight of water, for example from about 10% to about 20% by weight ofwater, such as from about 10% to about 15% by weight of water, such asfrom about 15% to about 40% by weight of water, for example from about15% to about 30% by weight of water, such as from about 15% to about 25%by weight of water, for example from about 15% to about 20% by weight ofwater.

Absorbent Compound Comprising an Adhesive Surface

In a further embodiment the present invention relates one or more woundor tissue dressings comprising one or more absorbent compound(s) forabsorbing wound exudate, wherein said wound or tissue dressing has beenprinted with one or more pharmaceutical compositions and wherein saidabsorbent compound comprises an adhesive surface. Non-limiting examplesof an adhesive surface are given below.

The absorbent compound can comprise at least one adhesive surfacesuitable for contacting a wound or the absorbent compound can beattached to at least one adhesive surface suitable for contacting awound. When the absorbent compound is attached to at least one adhesivesurface suitable for contacting a wound the absorbent compound and theadhesive surface are most often manufactured separately and only broughttogether during the manufacturing of the wound or tissue dressingaccording to the present invention. The adhesive surface can simply bepositioned on or spread out over the corresponding surface of theabsorbent compound, such as the absorbent compound surface which isgoing to be aligned with the surface of a wound.

The at least one adhesive surface can be separated from the absorbentcompound by a permeable or semi-permeable barrier allowing woundextrudate to be diverted from the wound to the absorbent compound.Alternatively, the at least one adhesive surface can itself comprise abarrier acting as a permeable or semi-permeable barrier that allowswound extrudate to be diverted from the wound to the absorbent compound.

The absorbent compound can also be attached to a topfilm at least partlysealing the absorbent compound from the external environment.Alternatively, the absorbent compound itself comprises a functionalityacting as a topfilm at least partly sealing the absorbent compound fromthe external environment.

The topfilm is often porous and the topfilm can comprise an oxygen- andvapor-permeable layer permitting transpiration of liquid from theabsorbent compound.

Gelatin and Collagen Absorbent Compounds

In some embodiments the wound or tissue dressing according to thepresent invention comprises an absorbent compound comprising orconsisting of gelatin and/or collagen, including a combination ofgelatin and collagen.

When the absorbent compound comprises or consists of gelatin the gelatincan be cross-linked and form a matrix, such as a matrix in the form of ahydrogel.

Alternatively, the wound or tissue dressing can comprise or consist ofgelatin which is not crosslinked. The gelatin can be in granulated orparticulated form and most often such dressings employ hydrocolloids.

When the absorbent compound comprises or consists of collagen thecollagen can be cross-linked and form a matrix, such as a matrix in theform of a hydrogel.

Alternatively, the wound or tissue dressing can comprise or consist ofcollagen which is not crosslinked. The collagen can be in granulated orparticulated form and most often such dressings employ hydrocolloids.

Hyaluronic acid can be present in the dressing in a haemostasispromoting amount in combination with any or both of gelatin andcollagen.

Alginate Absorbent Compounds

In one embodiment the absorbent compound comprises an optionallycross-linked alginate compound, such as an alginate ester, for examplean alginate ester comprising propylene glycol alginate.

The degree of esterification of the alginate ester is typically from 35%to 95% and the absorbent compound can contain from 10% to 25% by weightof the alginate ester.

Wound or Tissue Dressings Comprising Hydrocolloids

The wound or tissue dressing can comprise a hydrocolloid, but in someembodiments the hydrocolloid can be omitted. In embodiments wherein ahydrocolloid is used, the hydrocolloid comprises about 20 to about 60weight percent of the wound or tissue dressing, based on total weight.

The hydrocolloid can comprise e.g. from about 25 to about 55 weightpercent of the composition, such as from about 30 to about 50 weightpercent of the composition. In one embodiment, the hydrocolloidcomprises about 40 weight percent of the composition.

The hydrocolloid used in the present invention can be syntheticallyprepared or naturally occurring. Varieties of hydrocolloids within thescope of the present invention include synthetic polymers prepared fromsingle or multiple monomers, naturally occurring hydrophilic polymers,or chemically modified naturally occurring hydrophilic polymers. It ispreferred that the hydrocolloid is dermatologically acceptable andnon-reactive with the skin of the patient or other components of thecomposition. Preferred examples are hydrocolloids comprising gelatinand/or collagen.

Further specific examples include hydrocolloids comprising e.g.polyhydroxyalkyl acrylates and methacrylates, polyvinyl lactams,polyvinyl alcohols, polyoxyalkylenes, polyacrylamides, polyacrylic acid,polystyrene sulfonates, natural or synthetically modifiedpolysaccharides, alginates, gums, and cellulosics and modifiedcelluloses.

Representative polysaccharides include e.g. starch, glycogen,hemicelluloses, pentosans, celluloses, pectin, chitosan, and chitin.

Representative gums include e.g. Arabic, Locust Bean, Guar, Agar,Carrageenan, Xanthan, Karaya, tragacanth, Ghatti, and Furcelleran gums.

Representative modified celluloses include methyl cellulose,hydroxypropyl methyl cellulose, carboxymethylcellulose, andhydroxypropyl cellulose.

Hydrocolloids which are water soluble or swellable hydrocolloids can beselected e.g. from the group consisting of polyvinyl alcohols, powderedpectin, methyl cellulose, hydroxypropyl methyl cellulose,carboxymethylcellulose, hydroxypropyl cellulose and mixtures thereof.

Further examples of suitable hydrocolloids include synthetic polymersthat may be either linear or crosslinked. Non-limiting examples ofsynthetic hydrocolloids include e.g. polymers prepared from N-vinyllactams, e.g. N-vinyl-2-pyrrolidone, 5-methyl-N-vinyl-2-pyrrolidone,5-ethyl-N-vinyl-2-pyrrolidone, 3,3-dimethyl-N-vinyl-2-pyrrolidone,3-methyl-N-vinyl-2-pyrrolidone, 3-ethyl-N-vinyl-2-pyrrolidone,4-methyl-N-vinyl-2-pyrrolidone, 4-ethyl-N-vinyl-2-pyrrolidone,N-vinyl-2-valerolactam, and N-vinyl-2-caprolactam.

Other monomers useful to prepare a synthetic hydrocolloid includehydroxyalkyl acrylates and methacrylates, (such as 2-hydroxyethylacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate,2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate), acrylicacid, methacrylic acid and a tertiary amino-methacrylimide, (e.g.trimethylamino-methacrylimide), crotonic acid, and pyridine. Additionalmonomers useful to prepare a synthetic hydrocolloid include watersoluble amides, (such as N-(hydroxymethyl)acrylamide and-methacrylamide, N-(3-hydroxpropyl)acrylamide,N-(2-hydroxyethyl)methacrylamide, N-(1,1-dimethyl-3-oxabutyl)acrylamideN-[2-(dimethylamine)ethyl]acrylamide and -methacrylamide,N-[3-(dimethylamino)-2-hydroxylpropyl]methacrylamide, andN-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide); water-solublehydrazine derivatives, (such as trialkylamine methacrylimide, anddimethyl-(2-hydroxypropyl)amine methacrylimide); mono-olefinic sulfonicacids and their salts, (such as sodium ethylene sulfonate, sodiumstyrene sulfonate and 2-acrylamideo-2-methylpropanesulfonic acid); andthe following monomers containing nitrogen in the non-cyclic or cyclicbackbone of the monomer: 1-vinyl-imidazole, 1-vinyl-indole, 2-vinylimidazole, 4(5)-vinyl-imidazole, 2-vinyl-1-methyl-imidazole,5-vinyl-pyrazoline, 3-methyl-5-isopropenyl-pyrazole,5-methylene-hydantoin, 3-vinyl-2-oxazolidone,3-methacrylyl-2-oxazolidone, 3-methacrylyl-5-methyl-2-oxazolidone,3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinyl-pyridine,5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1-oxide,3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine, and4-acrylyl-morpholine.

Hydrogels

Cross-linking of the linear polymer chains of the hydrocolloid may bedesired to improve cohesive properties of the gel dispersed in thepressure sensitive adhesive matrix. When such crosslinking is desiredfor polymers made from vinyl monomers discussed above, amulti-ethylenically unsaturated compound with the ethylenic groups beingvinyl, allyl, or methallyl groups bonded to nitrogen, oxygen or carbonatoms can be used.

Non-limiting examples of cross-linking agents for vinyl containingpolymers include divinyl, diallyl, or dimethallyl esters (e.g. ethyleneglycol dimethacrylate, divinyl succinate, divinyl adipate, divinylmaleate, divinyl oxalate, divinyl malonate, divinyl glutarate, diallylitaconate, diallyl maleate, diallyl fumarate, diallyl diglycolate,diallyl oxalate, diallyl adipate, diallyl succinate, diallyl azelate,diallyl malonate, diallyl glutarate, dimethallyl maleate, dimethallyloxalate, dimethallyl malonate, dimethallyl succinate, dimethallylglutarate, and dimethallyl adipate); divinyl, diallyl or dimethallylethers (e.g. diethyleneglycol divinyl ether, butane diol divinyl ether,ethylene glycol divinyl ether, ethylene glycol diallyl ether, diethyleneglycol diallyl ether, butane diol diallyl ether, ethylene glycoldimethallyl ether, diethylene glycol dimethallyl ether, and butane dioldimethallyl ether); divinyl, diallyl or dimethallyl amides includingbis(N-vinyl lactams), (e.g., 3,3′-ethylene bis(N-vinyl-2-pyrrolidone)and methylene-bis-acrylamide); and divinyl, diallyl and dimethallylureas.

Preferred cross-linking agents include ethylene glycol dimethacrylate,methylene-bis-acrylamide, diallyl maleate, and 3,3′-ethylidenebis(N-vinyl-2-pyrrolidone). For n-vinyl lactams, the preferredcrosslinking agents are diallyl maleate and 3,3′-ethylidenebis(N-vinyl-2-pyrrolidone). For acrylates and methacrylates, thepreferred crosslinking agents are ethylene glycol dimethacrylate andmethylene-bis-acrylamide.

Wound or Tissue Dressings Comprising Humectants

The dressing can also contain a humectant to reduce the partial vaporpressure of the water in the wound or tissue dressing or to reduce therate at which the wound or tissue dressing dries out. Suitablehumectants are miscible with water to a large extent and are generallysuitable for application to the skin.

The humectant can be e.g. glycerol and propylene glycol and theabsorbent compound typically contains from about 10% to about 90% byweight of the humectant. Polyols are especially suitable for the purposeand suitable polyols may include monopropylene glycol or glycerin(glycerol). The polyol may be present in proportions of 20 to 50% (byweight) of the total formulation; alternatively the range is 30 to 40%.This relatively high proportion of polyol also ensures that if the pasteshould dry out to any degree, the resulting paste remains soft andflexible because the glycerin may act as a plasticiser for the polymer.When the paste is applied on a bandage, for example, it may thereforestill be removed easily from the skin when the paste has lost waterwithout the need to cut the bandage off. The polyol also has theadvantage of functioning to prevent the proliferation of bacteria in thepaste when it is in contact with the skin or wound, particularlyinfected wounds.

Method for Manufacturing Wound or Tissue Dressings According to theInvention

The present method is also directed to a method for manufacturing thewound or tissue dressing according to the invention, said methodcomprising the steps of providing one or more pharmaceuticalcompositions, and printing said one or more pharmaceutical compositionsonto the wound or tissue dressing and/or with the absorbent compound ofthe wound or tissue dressing, thereby obtaining the wound or tissuedressing according to the invention.

The method can comprise the further step of providing the absorbentcompound with at least one adhesive surface suitable for contacting awound, or the further step of attaching at least one adhesive surfacesuitable for contacting a wound to the absorbent compound.

In another further step there is provided a permeable or semi-permeablebarrier for separating the at least one adhesive surface from theabsorbent compound by introducing said permeable or semi-permeablebarrier between the absorbent compound and the at least one adhesivesurface, wherein said permeable or semi-permeable barrier allows woundextrudate to be diverted from the wound to the absorbent compound.

In a yet further step the method comprises providing a permeable orsemi-permeable barrier capable of partly separating—during use—the atleast one adhesive surface from the wound by introducing said permeableor semi-permeable barrier on the surface of the adhesive surface,wherein said permeable or semi-permeable barrier—during use—allows woundextrudate to be diverted from the wound to the absorbent compoundthrough the adhesive surface.

In yet further step a topfilm can be provided and attached to theabsorbent compound, wherein said topfilm seals at least partly theabsorbent compound from the external environment. The absorbent compoundcan also comprise a topfilm as an integrated part, wherein said topfilmat least partly seals the absorbent compound from the externalenvironment. The topfilm can be porous or non-porous. In one embodiment,the topfilm comprises an oxygen- and vapor-permeable layer permittingtranspiration of liquid from the absorbent compound.

Wound Treatment Methods

Various uses of the wound or tissue dressings according to the presentinvention are envisaged. In one embodiment there is provided a methodfor treating a wound in an individual, said method comprising the stepsof contacting said wound with the wound or tissue dressing according tothe present invention, and treating the wound.

The treatment can in principle result in healing of the wound or inaccelerated healing of the wound. The accelerated healing can be aresult of e.g. administration of a wound-healing promoting substance.Alternatively, the wound healing can be promoted by preventing bacterialor viral infection, or by reducing the risk of such an infection whichwould otherwise have prolonged the wound treatment process.

In another embodiment there is provided a method for treating damagedtissue in an individual, said method comprising the steps of contactingsaid damaged tissue with the wound or tissue dressing according to theinvention, and treating the damaged tissue.

Likewise, the treatment can in principle result in healing of thedamaged tissue or in accelerated healing of the damaged tissue. Theaccelerated healing can be a result a e.g. administration of atissue-healing promoting substance. Alternatively, the healing ofdamaged tissue can be promoted by preventing bacterial or viralinfection, or by reducing the risk of such an infection which wouldotherwise have prolonged the treatment of the damaged tissue.

The tissue damage can e.g. be caused by bone protrudence, by diabetes,by circulatory insufficiencies or by undesirable inflammatory processesin an individual.

There is also provided a method for preventing or reducing the risk ofwound or tissue infection in an individual having suffered a wound ordamaged tissue, said method comprising the steps of contacting saidwound or tissue with the wound or tissue dressing according to theinvention, and treating the wound or tissue at risk of being infected.The infectious agent at risk of infecting the wound or tissue can be abacteria or a virus.

As e.g. gelatin and hyaluronic acid independently and in combinationhave a haemostatic effect, there is also provided a method for promotinghaemostasis in a wound in an individual, said method comprising thesteps of contacting said wound with the wound dressing printed with oneor more pharmaceutical compositions according to the invention, andpromoting haemostasis in the wound.

In addition to contacting a wound or damaged tissue with the wound ortissue dressing according to the invention, there is also providedcombination methods wherein one or more wound or tissuehealing-promoting substance(s) are administered simultaneously orsequentially in any order one or more at the same time as the wound ortissue to be treated is contacted with the wound or tissue dressingaccording to the invention. This may be of particular importance whentreating slow-healing wounds, partial thickness wound, deep wounds andchronic wounds.

Method for Manufacturing of Wound and/or Tissue Dressings

In a further aspect there is provided a method for manufacturing a woundor tissue dressing printed with one or more pharmaceutical compositionsaccording to the present invention, said method comprising the steps ofproviding one or more pharmaceutical compositions, printing said one ormore pharmaceutical compositions onto the wound or tissue dressingand/or onto the absorbent compound of the wound or tissue dressing,thereby obtaining a wound or tissue dressing according to the presentinvention.

There is also provided the use of printing of one or more pharmaceuticalcompositions for the manufacture of a wound or tissue dressing fortreating or accelerating the healing of a wound in an individual.

In yet another aspect there is provided the use of printing of one ormore pharmaceutical compositions for the manufacture of an absorbentcompound for use in a wound or tissue dressing for treating oraccelerating the healing of a wound in an individual.

The present invention also relates to the use of printing of one or morepharmaceutical compositions for the manufacture of an absorbent compoundfor use in a wound or tissue dressing for treating a wound or tissue oraccelerating the healing of a wound or tissue in an individual.

In a further embodiment the present invention relates to the use ofprinting of one or more pharmaceutical compositions in the manufactureof a wound or tissue dressing for preventing or reducing the risk ofwound or tissue infection in an individual having suffered a wound.

The present invention also relates to the use of printing of one or morepharmaceutical compositions in the manufacture of a wound or tissuedressing for promoting haemostasis in a wound in an individual.

A Container for Storage and/or Preparation of a Matrix Material

The present invention also relates to a container, box or packagingmeans e.g. for storage and/or preparation of a matrix material. In oneembodiment this container, box or packaging provides a sterileenvironment for storage and/or preparation of the matrix material.

The container comprises an inner cavity (hollow space) for storage of amatrix material. In one embodiment the container comprises more than oneinner cavity for storage of more than one matrix material such as 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99 or 100 inner cavities, for storage of more than onematrix material such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 matrix materials.

In another embodiment, the container comprises one inner cavity forstorage of more than one matrix material such as 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 41, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99or 100 matrix materials.

The inner cavity is made of a bottom with defined dimensions, and one ormore sidewall(s) with a defined height. The one or more sidewalls of thecavity comprise in one embodiment a mark for the maximum volume thatshould be added to the cavity containing the matrix material. This markcan be any type of mark such as a line, dot or the one or more sides cancomprise a bend e.g. the angle between the bottom and the side differbetween the sidewall below and above the mark—i.e. one or more bevellededges as a guiding tool for maximum amount of liquid/moisture to beadded to the inner cavity containing the one or more matrix material(s).One advantage of the container is that the one or more mark(s) on theone or more sidewall(s) decreases the risk of addition of excess liquidto the container comprising one or more matrix materials.

The cavity should generally circumvent the matrix material. Accordingly,the shape of the cavity should be adjusted to fit or surround the shapeof the matrix material.

The cavity defined by the size of the bottom of the inner cavity and theheight of one or more sidewalls measured from the bottom of the innercavity to the mark for maximum filling is referred to as the maximumvolume of liquid to be added to the container comprising the matrixmaterial.

In one embodiment the maximum volume of liquid to be added to thecontainer comprising the matrix material is in the range of from 1 mL to60 mL, such as from 1 mL to 2 mL, for example from 2 to 3 mL, such asfrom 3 mL to 4 mL, for example from 4 to 5 mL, such as from 5 mL to 6mL, for example from 6 to 7 mL, such as from 7 mL to 8 mL, for examplefrom 8 to 9 mL, such as from 9 mL to 10 mL, for example from 10 to 11mL, such as from 11 mL to 12 mL, for example from 12 to 13 mL, such asfrom 13 mL to 14 mL, for example from 14 to 15 mL, such as from 15 mL to16 mL, for example from 16 to 17 mL, such as from 17 mL to 18 mL, forexample from 18 to 19 mL, such as from 19 mL to 20 mL, for example from20 to 21 mL, such as from 21 mL to 22 mL, for example from 22 to 23 mL,such as from 23 mL to 24 mL, for example from 24 to 25 mL, such as from25 mL to 26 mL, for example from 26 to 27 mL, such as from 27 mL to 28mL, for example from 28 to 29 mL, such as from 29 mL to 30 mL, forexample from 30 to 31 mL, such as from 31 mL to 32 mL, for example from32 to 33 mL, such as from 33 mL to 34 mL, for example from 34 to 35 mL,such as from 35 mL to 36 mL, for example from 36 to 37 mL, such as from37 mL to 38 mL, for example from 38 to 39 mL, such as from 39 mL to 40mL, for example from 40 to 41 mL, such as from 41 mL to 42 mL, forexample from 42 to 43 mL, such as from 43 mL to 44 mL, for example from44 to 45 mL, such as from 45 mL to 46 mL, for example from 46 to 47 mL,such as from 47 mL to 48 mL, for example from 48 to 49 mL, such as from49 mL to 50 mL, for example from 50 to 51 mL, such as from 51 mL to 52mL, for example from 52 to 53 mL, such as from 53 mL to 54 mL, forexample from 54 to 55 mL, such as from 55 mL to 56 mL, for example from56 to 57 mL, such as from 57 mL to 58 mL, for example from 58 to 59 mL,such as from 59 mL to 60 mL. The maximum volume of liquid to be added tothe container comprising the matrix material will depend on factors suchas size of the cavity of the container and the liquid absorbability ofthe matrix material used.

In one embodiment the maximum volume of liquid to be added to thecontainer should be in range of from 5% to 50% of the volume of thematrix material such as from 5% to 6%, for example from 6% to 7%, suchas from 7% to 8%, for example from 8% to 9%, such as from 9% to 10%, forexample from 10% to 11%, such as from 11% to 12%, for example from 12%to 13%, such as from 13% to 14%, for example from 14% to 15%, such asfrom 15% to 16%, for example from 16% to 17%, such as from 17% to 18%,for example from 18% to 19%, such as from 19% to 20%, for example from20% to 21%, such as from 21% to 22%, for example from 22% to 23%, suchas from 23% to 24%, for example from 24% to 25%, such as from 25% to26%, for example from 26% to 27%, such as from 27% to 28%, for examplefrom 28% to 29%, such as from 29% to 30%, for example from 30% to 31%,such as from 31% to 32%, for example from 32% to 33%, such as from 33%to 34%, for example from 34% to 35%, such as from 35% to 36%, forexample from 36% to 37%, such as from 37% to 38%, for example from 38%to 39%, such as from 39% to 40%, for example from 40% to 41%, such asfrom 41% to 42%, for example from 42% to 43%, such as from 43% to 44%,for example from 44% to 45%, such as from 45% to 46%, for example from46% to 47%, such as from 47% to 48%, for example from 48% to 49%, orsuch as from 49% to 50%.

In one embodiment the preferred volume of liquid to be added to thecontainer should be in range of from 5% to 50% of the volume of theinner cavity such as from 5% to 6%, for example from 6% to 7%, such asfrom 7% to 8%, for example from 8% to 9%, such as from 9% to 10%, forexample from 10% to 11%, such as from 11% to 12%, for example from 12%to 13%, such as from 13% to 14%, for example from 14% to 15%, such asfrom 15% to 16%, for example from 16% to 17%, such as from 17% to 18%,for example from 18% to 19%, such as from 19% to 20%, for example from20% to 21%, such as from 21% to 22%, for example from 22% to 23%, suchas from 23% to 24%, for example from 24% to 25%, such as from 25% to26%, for example from 26% to 27%, such as from 27% to 28%, for examplefrom 28% to 29%, such as from 29% to 30%, for example from 30% to 31%,such as from 31% to 32%, for example from 32% to 33%, such as from 33%to 34%, for example from 34% to 35%, such as from 35% to 36%, forexample from 36% to 37%, such as from 37% to 38%, for example from 38%to 39%, such as from 39% to 40%, for example from 40% to 41%, such asfrom 41% to 42%, for example from 42% to 43%, such as from 43% to 44%,for example from 44% to 45%, such as from 45% to 46%, for example from46% to 47%, such as from 47% to 48%, for example from 48% to 49%, orsuch as from 49% to 50%.

In one embodiment the preferred volume of liquid to be added to thecontainer should be in range of from 1 mL to 60 mL, such as from 1 mL to2 mL, for example from 2 to 3 mL, such as from 3 mL to 4 mL, for examplefrom 4 to 5 mL, such as from 5 mL to 6 mL, for example from 6 to 7 mL,such as from 7 mL to 8 mL, for example from 8 to 9 mL, such as from 9 mLto 10 mL, for example from 10 to 11 mL, such as from 11 mL to 12 mL, forexample from 12 to 13 mL, such as from 13 mL to 14 mL, for example from14 to 15 mL, such as from 15 mL to 16 mL, for example from 16 to 17 mL,such as from 17 mL to 18 mL, for example from 18 to 19 mL, such as from19 mL to 20 mL, for example from 20 to 21 mL, such as from 21 mL to 22mL, for example from 22 to 23 mL, such as from 23 mL to 24 mL, forexample from 24 to 25 mL, such as from 25 mL to 26 mL, for example from26 to 27 mL, such as from 27 mL to 28 mL, for example from 28 to 29 mL,such as from 29 mL to 30 mL, for example from 30 to 31 mL, such as from31 mL to 32 mL, for example from 32 to 33 mL, such as from 33 mL to 34mL, for example from 34 to 35 mL, such as from 35 mL to 36 mL, forexample from 36 to 37 mL, such as from 37 mL to 38 mL, for example from38 to 39 mL, such as from 39 mL to 40 mL, for example from 40 to 41 mL,such as from 41 mL to 42 mL, for example from 42 to 43 mL, such as from43 mL to 44 mL, for example from 44 to 45 mL, such as from 45 mL to 46mL, for example from 46 to 47 mL, such as from 47 mL to 48 mL, forexample from 48 to 49 mL, such as from 49 mL to 50 mL, for example from50 to 51 mL, such as from 51 mL to 52 mL, for example from 52 to 53 mL,such as from 53 mL to 54 mL, for example from 54 to 55 mL, such as from55 mL to 56 mL, for example from 56 to 57 mL, such as from 57 mL to 58mL, for example from 58 to 59 mL, such as from 59 mL to 60 mL.

In one embodiment the container is made of plastic and has an exterior,an interior and a sealed outer periphery, the sealed outer peripheryforming a sterile interior region which isolates the interior from asurrounding environment. A matrix material is located within theinterior and is initially isolated from the surrounding environment bythe sealed periphery.

In one embodiment the container comprises a bottom, one or moresidewalls, a mark for maximum filling of the container on one or more ofthe sidewalls, a sealing surface for a lid and a lid (e.g., as shown inFIGS. 2A and 2B, FIGS. 3A and 3B, FIG. 4, FIG. 5 and FIG. 6). Thecontainer can comprise one or more inner tray notches that make it easyto handle the matrix material without destroying the structure of thematrix material (e.g., as shown in FIGS. 2A and 2B, FIG. 4 and FIG. 5).In one embodiment the container has a base to provide stabile placementon all possible surfaces such as even or uneven surfaces including asterile field, a mayo stand, a tray of instruments or on the chest ofthe patient (e.g., as shown in FIGS. 2A and 2B, FIGS. 3A and 3B, FIG. 4,FIG. 5 and FIG. 6). The base can provide stability during handling tominimize the risk of spilling. The container optionally also has ahandle (e.g., as shown in FIGS. 2A and 2B, FIGS. 3A and 3B, FIG. 4, FIG.5 and FIG. 6).

In one embodiment the bottom, base, sidewalls and optionally handle ofthe container is cast or moulded in one piece of e.g. plastic. Thebottom, base, sidewalls and optionally handle of the container can alsobe cast or moulded in more than one piece of e.g. plastic such as 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or more than 12 pieces of e.g. plastic. Inone preferred embodiment, the container contains a handle and thebottom, base, sidewalls and handle are cast or moulded in one piece.

In one embodiment the bottom and lid and/or the bottom and the baseand/or the base and the lid are parallel. In another embodiment thebottom and lid and/or the bottom and the base and/or the base and thelid are not parallel. In one embodiment the lid and/or the base and/orthe bottom of the container is perpendicular to the one or moresidewalls of the container. In one embodiment the lid and/or the baseand/or the bottom of the container is not perpendicular to the one ormore sidewalls of the container. The angle between the lid and/or thebase and/or the bottom of the container and the one or more sidewallscan be in the range of from 20 degrees to 160 degrees, such as from 20degrees to 25 degrees, for example from 25 degrees to 30 degrees, suchas from 30 degrees to 35 degrees, for example from 35 degrees to 40degrees, such as from 40 degrees to 45 degrees, for example from 45degrees to 50 degrees, such as from 50 degrees to 55 degrees, forexample from 55 degrees to 60 degrees, such as from 60 degrees to 65degrees, for example from 65 degrees to 70 degrees, such as from 70degrees to 75 degrees, for example from 75 degrees to 80 degrees, suchas from 80 degrees to 85 degrees, for example from 85 degrees to 90degrees, such as from 90 degrees to 95 degrees, for example from 95degrees to 100 degrees, such as from 100 degrees to 105 degrees, forexample from 105 degrees to 110 degrees, such as from 110 degrees to 115degrees, for example from 115 degrees to 120 degrees, such as from 120degrees to 125 degrees, for example from 125 degrees to 130 degrees,such as from 130 degrees to 135 degrees, for example from 135 degrees to140 degrees, such as from 140 degrees to 145 degrees, for example from145 degrees to 150 degrees, such as from 150 degrees to 155 degrees, forexample from 155 degrees to 160 degrees.

The bottom of the cavity of the container can be any shape such as asquare, rectangle, triangle, circle, or oval:

In one embodiment the bottom is formed as a square e.g. with thedimensions of 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1 cm×5 cm, 1cm×6 cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1 cm×15 cm, 1cm×20 cm, 2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2 cm×5 cm, 2 cm×6cm, 2 cm×7 cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2 cm×15 cm, 2 cm×20 cm,3 cm×1 cm, 3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3 cm×5 cm, 3 cm×6 cm, 3 cm×7cm, 3 cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3 cm×15 cm, 3 cm×20 cm, 4 cm×1 cm,4 cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4 cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4 cm×8cm, 4 cm×9 cm, 4 cm×10 cm, 4 cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5 cm×2 cm,5 cm×3 cm, 5 cm×4 cm, 5 cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8 cm, 5 cm×9cm, 5 cm×10 cm, 5 cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm, 6 cm×3 cm,6 cm×4 cm, 6 cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9 cm, 6cm×10 cm, 6 cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm, 7cm×4 cm, 7 cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7 cm×10cm, 7 cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8 cm×4 cm,8 cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9 cm×5cm, 9 cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9 cm×15 cm,9 cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4 cm, 10 cm×5 cm,10 cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10 cm×10 cm, 10 cm×15cm, 10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3 cm, 11 cm×4 cm, 11 cm×5cm, 11 cm×6 cm, 11 cm×7 cm, 11 cm×8 cm, 11 cm×9 cm, 11 cm×10 cm, 11cm×15 cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2 cm, 12 cm×3 cm, 12 cm×4 cm,12 cm×5 cm, 12 cm×6 cm, 12 cm×7 cm, 12 cm×8 cm, 12 cm×9 cm, 12 cm×10 cm,12 cm×15 cm, 12 cm×20 cm, 13 cm×1 cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4cm, 13 cm×5 cm, 13 cm×6 cm, 13 cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13 cm×10cm, 13 cm×15 cm, 13 cm×20 cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm, 14cm×4 cm, 14 cm×5 cm, 14 cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm, 14cm×10 cm, 14 cm×15 cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3 cm,15 cm×4 cm, 15 cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm,15 cm×10 cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3cm, 16 cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9cm, 16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm, 17cm×9 cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18 cm×2 cm,18 cm×3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm, 18 cm×8 cm,18 cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19 cm×1 cm, 19 cm×2cm, 19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm, 19 cm×7 cm, 19 cm×8cm, 19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19 cm×20 cm, 20 cm×1 cm, 20cm×2 cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5 cm, 20 cm×6 cm, 20 cm×7 cm, 20cm×8 cm, 20 cm×9 cm, 20 cm×10 cm, 20 cm×15 cm, 20 cm×20 cm, 25 cm×1 cm,25 cm×2 cm, 25 cm×3 cm, 25 cm×4 cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm,25 cm×8 cm, 25 cm×9 cm, 25 cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1cm, 30 cm×2 cm, 30 cm×3 cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7cm, 30 cm×8 cm, 30 cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40cm×1 cm, 40 cm×2 cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40cm×7 cm, 40 cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm,50 cm×1 cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm,50 cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50cm×20 cm.

The dimensions of the bottom of the container may also be any decimalnumber, for example 13.035 cm×9.74 cm (small), such as 13.035 cm×13.73cm (medium) or for example 13.035 cm×20.04 cm (large).

In another embodiment the bottom is formed as a square e.g. with thedimensions of between 1 cm² to 500 cm², such as 1 cm² to 5 cm², forexample 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as50 cm² to 60 cm², for example 60 cm² to 70 cm², such as 70 cm² to 80cm², for example 80 cm² to 90 cm², such as 90 cm² to 100 cm², forexample 100 cm² to 110 cm², such as 110 cm² to 120 cm², for example 120cm² to 130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150cm², such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², forexample 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example 240cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm² to 270cm², such as 270 cm² to 280 cm², for example 280 cm² to 290 cm², such as290 cm² to 300 cm², for example 300 cm² to 320 cm², such as 320 cm² to340 cm², for example 340 cm² to 360 cm², such as 360 cm² to 380 cm², forexample 380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420cm² to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480cm², such as 480 cm² to 500 cm².

It follows that the dimension of the square bottom need not be a wholeor counting number, but may also be any decimal number.

In one embodiment the bottom is formed to circumvent a matrix materialshaped as a square with one of the dimensions selected from the groupconsisting of 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1 cm×5 cm, 1cm×6 cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1 cm×15 cm, 1cm×20 cm, 2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2 cm×5 cm, 2 cm×6cm, 2 cm×7 cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2 cm×15 cm, 2 cm×20 cm,3 cm×1 cm, 3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3 cm×5 cm, 3 cm×6 cm, 3 cm×7cm, 3 cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3 cm×15 cm, 3 cm×20 cm, 4 cm×1 cm,4 cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4 cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4 cm×8cm, 4 cm×9 cm, 4 cm×10 cm, 4 cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5 cm×2 cm,5 cm×3 cm, 5 cm×4 cm, 5 cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8 cm, 5 cm×9cm, 5 cm×10 cm, 5 cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm, 6 cm×3 cm,6 cm×4 cm, 6 cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9 cm, 6cm×10 cm, 6 cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm, 7cm×4 cm, 7 cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7 cm×10cm, 7 cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8 cm×4 cm,8 cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9 cm×5cm, 9 cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9 cm×15 cm,9 cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4 cm, 10 cm×5 cm,10 cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10 cm×10 cm, 10 cm×15cm, 10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3 cm, 11 cm×4 cm, 11 cm×5cm, 11 cm×6 cm, 11 cm×7 cm, 11 cm×8 cm, 11 cm×9 cm, 11 cm×10 cm, 11cm×15 cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2 cm, 12 cm×3 cm, 12 cm×4 cm,12 cm×5 cm, 12 cm×6 cm, 12 cm×7 cm, 12 cm×8 cm, 12 cm×9 cm, 12 cm×10 cm,12 cm×15 cm, 12 cm×20 cm, 13 cm×1 cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4cm, 13 cm×5 cm, 13 cm×6 cm, 13 cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13 cm×10cm, 13 cm×15 cm, 13 cm×20 cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm, 14cm×4 cm, 14 cm×5 cm, 14 cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm, 14cm×10 cm, 14 cm×15 cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3 cm,15 cm×4 cm, 15 cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm,15 cm×10 cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3cm, 16 cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9cm, 16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm, 17cm×9 cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18 cm×2 cm,18 cm x3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm, 18 cm×8 cm,18 cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19 cm×1 cm, 19 cm×2cm, 19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm, 19 cm×7 cm, 19 cm×8cm, 19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19 cm×20 cm, 20 cm×1 cm, 20cm×2 cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5 cm, 20 cm×6 cm, 20 cm×7 cm, 20cm×8 cm, 20 cm×9 cm, 20 cm×10 cm, 20 cm×15 cm, 20 cm×20 cm, 25 cm×1 cm,25 cm×2 cm, 25 cm×3 cm, 25 cm×4 cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm,25 cm×8 cm, 25 cm×9 cm, 25 cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1cm, 30 cm×2 cm, 30 cm×3 cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7cm, 30 cm×8 cm, 30 cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40cm×1 cm, 40 cm×2 cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40cm×7 cm, 40 cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm,50 cm×1 cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm,50 cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50cm×20 cm.

In one embodiment the bottom is formed to circumvent a matrix materialshaped as a square with a dimension of between 1 cm² to 500 cm², such as1 cm² to 5 cm², for example 5 cm² to 10 cm², such as 10 cm² to 20 cm²,for example 20 cm² to 30 cm², such as 30 cm² to 40 cm², for example 40cm² to 50 cm², such as 50 cm² to 60 cm², for example 60 cm² to 70 cm²,such as 70 cm² to 80 cm², for example 80 cm² to 90 cm², such as 90 cm²to 100 cm², for example 100 cm² to 110 cm², such as 110 cm² to 120 cm²,for example 120 cm² to 130 cm², such as 130 cm² to 140 cm², for example140 cm² to 150 cm², such as 150 cm² to 160 cm², for example 160 cm² to170 cm², such as 170 cm² to 180 cm², for example 180 cm² to 190 cm²,such as 190 cm² to 200 cm², for example 200 cm² to 210 cm², such as 210cm² to 220 cm², for example 220 cm² to 230 cm², such as 230 cm² to 240cm², for example 240 cm² to 250 cm², such as 250 cm² to 260 cm², forexample 260 cm² to 270 cm², such as 270 cm² to 280 cm², for example 280cm² to 290 cm², such as 290 cm² to 300 cm², for example 300 cm² to 320cm², such as 320 cm² to 340 cm², for example 340 cm² to 360 cm², such as360 cm² to 380 cm², for example 380 cm² to 400 cm², such as 400 cm² to420 cm², for example 420 cm² to 440 cm², such as 440 cm² to 460 cm², forexample 460 cm² to 480 cm², such as 480 cm² to 500 cm².

It follows that the dimension of the square matrix material need not bea whole or counting number, but may also be any decimal number.

In another embodiment the bottom is formed as a circle e.g. with adiameter in the range of from 1 cm to 40 cm, such as from 1 cm to 2 cm,for example from 2 cm to 4 cm, such as from 4 cm to 6 cm, for examplefrom 6 cm to 8 cm, such as from 8 cm to 10 cm, for example from 10 cm to12 cm, such as from 12 cm to 14 cm, for example from 14 cm to 16 cm,such as from 16 cm to 18 cm, for example from 18 cm to 20 cm, such asfrom 20 cm to 22 cm, for example from 22 cm to 24 cm, such as from 24 cmto 26 cm, for example from 26 cm to 28 cm, such as from 28 cm to 30 cm,for example from 30 cm to 32 cm, such as from 32 cm to 34 cm, forexample from 34 cm to 36 cm, such as from 36 cm to 38 cm, for examplefrom 38 cm to 40 cm.

In one embodiment the bottom is formed as a circle e.g. with a diameterof 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 5.5 cm,6 cm, 6.5 cm, 7 cm, 7.5 cm, 8 cm, 8.5 cm, 9 cm, 9.5 cm, 10 cm, 11 cm, 12cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 21 cm, 22cm, 23 cm, 24 cm, 25 cm, 26 cm, 27 cm, 28 cm, 29 cm, 30 cm, 31 cm, 32cm, 33 cm, 34 cm, 35 cm, 36 cm, 37 cm, 38 cm, 39 cm or 40 cm.

In one embodiment the bottom is formed as a circle e.g. with thedimensions of between 1 cm² to 500 cm², such as 1 cm² to 5 cm², forexample 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as50 cm² to 60 cm², for example 60 cm² to 70 cm², such as 70 cm² to 80cm², for example 80 cm² to 90 cm², such as 90 cm² to 100 cm², forexample 100 cm² to 110 cm², such as 110 cm² to 120 cm², for example 120cm² to 130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150cm², such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², forexample 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example 240cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm² to 270cm², such as 270 cm² to 280 cm², for example 280 cm² to 290 cm², such as290 cm² to 300 cm², for example 300 cm² to 320 cm², such as 320 cm² to340 cm², for example 340 cm² to 360 cm², such as 360 cm² to 380 cm², forexample 380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420cm² to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480cm², such as 480 cm² to 500 cm².

It follows that the dimension of the circular bottom need not be a wholeor counting number, but may also be any decimal number.

In one embodiment the bottom is formed as a circle e.g. with a diameterthat can circumvent a matrix material such as a circular matrix materialwith a diameter in the range of from 1 cm to 40 cm, such as from 1 cm to2 cm, for example from 2 cm to 4 cm, such as from 4 cm to 6 cm, forexample from 6 cm to 8 cm, such as from 8 cm to 10 cm, for example from10 cm to 12 cm, such as from 12 cm to 14 cm, for example from 14 cm to16 cm, such as from 16 cm to 18 cm, for example from 18 cm to 20 cm,such as from 20 cm to 22 cm, for example from 22 cm to 24 cm, such asfrom 24 cm to 26 cm, for example from 26 cm to 28 cm, such as from 28 cmto 30 cm, for example from 30 cm to 32 cm, such as from 32 cm to 34 cm,for example from 34 cm to 36 cm, such as from 36 cm to 38 cm, forexample from 38 cm to 40 cm.

In one embodiment the bottom is formed as a circle e.g. with a diameterthat can circumvent a matrix material such as a circular matrix materialwith a diameter of from of 1 cm, 2, cm, 3, cm, 4, cm, 5, cm, 6 cm, 7 cm,8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18cm, 19 cm, 20 cm, 21 cm, 22 cm, 23 cm, 24 cm, 25 cm, 26 cm, 27 cm, 28cm, 29 cm, 30 cm, 31 cm, 32 cm, 33 cm, 34 cm, 35 cm, 36 cm, 37 cm, 38cm, 39 cm or 40 cm.

In one embodiment the bottom is formed as a circle e.g. with a diameterthat can circumvent a matrix material such as a circular matrix materialwith a dimension of between 1 cm² to 500 cm², such as 1 cm² to 5 cm²,for example 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20cm² to 30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50 cm²,such as 50 cm² to 60 cm², for example 60 cm² to 70 cm², such as 70 cm²to 80 cm², for example 80 cm² to 90 cm², such as 90 cm² to 100 cm², forexample 100 cm² to 110 cm², such as 110 cm² to 120 cm², for example 120cm² to 130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150cm², such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², forexample 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example 240cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm² to 270cm², such as 270 cm² to 280 cm², for example 280 cm² to 290 cm², such as290 cm² to 300 cm², for example 300 cm² to 320 cm², such as 320 cm² to340 cm², for example 340 cm² to 360 cm², such as 360 cm² to 380 cm², forexample 380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420cm² to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480cm², such as 480 cm² to 500 cm².

It follows that the dimension of the circular matrix material need notbe a whole or counting number, but may also be any decimal number.

In one embodiment the height of the sidewalls (from the bottom to themark for maximum filling) is selected from the groups consisting of 0 mmto 2 mm, 2 mm to 4 mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mmto 12 mm, 12 mm to 14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20mm, 20 mm to 22 mm, 22 mm to 24 mm, 24 mm to 26 mm, 26 mm to 28 mm, 28mm to 30 mm, 30 mm to 32 mm, 32 mm to 34 mm, 34 mm to 36 mm, 36 mm to 38mm, 38 mm to 40 mm, 40 mm to 42 mm, 42 mm to 44 mm, 44 mm to 46 mm, 46mm to 48 mm or 48 mm to 50 mm.

In one embodiment the width of the sidewall(s) is in the range of 0 to20 mm, preferably selected from the groups consisting of 0 mm to 2 mm, 2mm to 4 mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mm to 12 mm,12 mm to 14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20 mm.

In one embodiment the height from the mark for maximum filling to thelid can be selected from the group consisting of 0 mm to 2 mm, 2 mm to 4mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mm to 12 mm, 12 mm to14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20 mm, 20 mm to 22 mm,22 mm to 24 mm, 24 mm to 26 mm, 26 mm to 28 mm, 28 mm to 30 mm, 30 mm to32 mm, 32 mm to 34 mm, 34 mm to 36 mm, 36 mm to 38 mm, 38 mm to 40 mm,40 mm to 42 mm, 42 mm to 44 mm, 44 mm to 46 mm, 46 mm to 48 mm or 48 mmto 50 mm.

In another embodiment the height from the bottom of the container to thelid of the container is selected from the groups consisting of 0 mm to 2mm, 2 mm to 4 mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mm to 12mm, 12 mm to 14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20 mm, 20mm to 22 mm, 22 mm to 24 mm, 24 mm to 26 mm, 26 mm to 28 mm, 28 mm to 30mm, 30 mm to 32 mm, 32 mm to 34 mm, 34 mm to 36 mm, 36 mm to 38 mm, 38mm to 40 mm, 40 mm to 42 mm, 42 mm to 44 mm, 44 mm to 46 mm, 46 mm to 48mm or 48 mm to 50 mm.

In one embodiment the cavity of the container also comprise space forcontacting the matrix material e.g. with scissors, tweezers, forceps,another device or one or more fingers (inner tray notches). Thecontainer can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10inner tray notches. These inner tray notches can have any size or formto provide easy contact with the matrix material. The one or more innertray notches may be associated with the one or more sidewall(s) of thecontainer.

The base of the container can have any shape such as a square,rectangle, triangle, circle, or oval.

In one embodiment the base is formed as a square e.g. with thedimensions 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1 cm×5 cm, 1 cm×6cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1 cm×15 cm, 1 cm×20 cm,2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2 cm×5 cm, 2 cm×6 cm, 2 cm×7cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2 cm×15 cm, 2 cm×20 cm, 3 cm×1 cm,3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3 cm×5 cm, 3 cm×6 cm, 3 cm×7 cm, 3 cm×8cm, 3 cm×9 cm, 3 cm×10 cm, 3 cm×15 cm, 3 cm×20 cm, 4 cm×1 cm, 4 cm×2 cm,4 cm×3 cm, 4 cm×4 cm, 4 cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4 cm×8 cm, 4 cm×9cm, 4 cm×10 cm, 4 cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5 cm×2 cm, 5 cm×3 cm,5 cm×4 cm, 5 cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8 cm, 5 cm×9 cm, 5cm×10 cm, 5 cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm, 6 cm×3 cm, 6cm×4 cm, 6 cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9 cm, 6 cm×10cm, 6 cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm, 7 cm×4 cm,7 cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7 cm×10 cm, 7cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8 cm×4 cm, 8 cm×5cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8 cm×15 cm,8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9 cm×5 cm, 9cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9 cm×15 cm, 9cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4 cm, 10 cm×5 cm, 10cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10 cm×10 cm, 10 cm×15 cm,10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3 cm, 11 cm×4 cm, 11 cm×5 cm,11 cm×6 cm, 11 cm×7 cm, 11 cm×8 cm, 11 cm×9 cm, 11 cm×10 cm, 11 cm×15cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2 cm, 12 cm×3 cm, 12 cm×4 cm, 12 cm×5cm, 12 cm×6 cm, 12 cm×7 cm, 12 cm×8 cm, 12 cm×9 cm, 12 cm×10 cm, 12cm×15 cm, 12 cm×20 cm, 13 cm×1 cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4 cm,13 cm×5 cm, 13 cm×6 cm, 13 cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13 cm×10 cm,13 cm×15 cm, 13 cm×20 cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm, 14 cm×4cm, 14 cm×5 cm, 14 cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm, 14 cm×10cm, 14 cm×15 cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3 cm, 15cm×4 cm, 15 cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm, 15cm×10 cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3 cm,16 cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9 cm,16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17 cm×3cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm, 17 cm×9cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18 cm×2 cm, 18cm×3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm, 18 cm×8 cm, 18cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19 cm×1 cm, 19 cm×2 cm,19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm, 19 cm×7 cm, 19 cm×8 cm,19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19 cm×20 cm, 20 cm×1 cm, 20 cm×2cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5 cm, 20 cm×6 cm, 20 cm×7 cm, 20 cm×8cm, 20 cm×9 cm, 20 cm×10 cm, 20 cm×15 cm, 20 cm×20 cm, 25 cm×1 cm, 25cm×2 cm, 25 cm×3 cm, 25 cm×4 cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm, 25cm×8 cm, 25 cm×9 cm, 25 cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1 cm,30 cm×2 cm, 30 cm×3 cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7 cm,30 cm×8 cm, 30 cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40 cm×1cm, 40 cm×2 cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40 cm×7cm, 40 cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm, 50cm×1 cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm, 50cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50 cm×20cm.

In one embodiment the bottom is formed as a square e.g. with thedimensions of between 1 cm² to 500 cm², such as 1 cm² to 5 cm², forexample 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as50 cm² to 60 cm², for example 60 cm² to 70 cm², such as 70 cm² to 80cm², for example 80 cm² to 90 cm², such as 90 cm² to 100 cm², forexample 100 cm² to 110 cm², such as 110 cm² to 120 cm², for example 120cm² to 130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150cm², such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², forexample 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example 240cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm² to 270cm², such as 270 cm² to 280 cm², for example 280 cm² to 290 cm², such as290 cm² to 300 cm², for example 300 cm² to 320 cm², such as 320 cm² to340 cm², for example 340 cm² to 360 cm², such as 360 cm² to 380 cm², forexample 380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420cm² to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480cm², such as 480 cm² to 500 cm².

It follows that the dimension of the square base need not be a whole orcounting number, but may also be any decimal number.

In one embodiment the base of the container is formed as a circle e.g.with a diameter in the range of from 1 cm to 40 cm, such as from 1 cm to2 cm, for example from 2 cm to 4 cm, such as from 4 cm to 6 cm, forexample from 6 cm to 8 cm, such as from 8 cm to 10 cm, for example from10 cm to 12 cm, such as from 12 cm to 14 cm, for example from 14 cm to16 cm, such as from 16 cm to 18 cm, for example from 18 cm to 20 cm,such as from 20 cm to 22 cm, for example from 22 cm to 24 cm, such asfrom 24 cm to 26 cm, for example from 26 cm to 28 cm, such as from 28 cmto 30 cm, for example from 30 cm to 32 cm, such as from 32 cm to 34 cm,for example from 34 cm to 36 cm, such as from 36 cm to 38 cm, forexample from 38 cm to 40 cm.

In one embodiment the base of the container is formed as a circle e.g.with a diameter of 1 cm, 2, cm, 3, cm, 4, cm, 5, cm, 6 cm, 7 cm, 8 cm, 9cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19cm, 20 cm, 21 cm, 22 cm, 23 cm, 24 cm, 25 cm, 26 cm, 27 cm, 28 cm, 29cm, 30 cm, 31 cm, 32 cm, 33 cm, 34 cm, 35 cm, 36 cm, 37 cm, 38 cm, 39 cmor 40 cm.

In one embodiment the bottom is formed as a circle e.g. with thedimensions of between 1 cm² to 500 cm², such as 1 cm² to 5 cm², forexample 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as50 cm² to 60 cm², for example 60 cm² to 70 cm², such as 70 cm² to 80cm², for example 80 cm² to 90 cm², such as 90 cm² to 100 cm², forexample 100 cm² to 110 cm², such as 110 cm² to 120 cm², for example 120cm² to 130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150cm², such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², forexample 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example 240cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm² to 270cm², such as 270 cm² to 280 cm², for example 280 cm² to 290 cm², such as290 cm² to 300 cm², for example 300 cm² to 320 cm², such as 320 cm² to340 cm², for example 340 cm² to 360 cm², such as 360 cm² to 380 cm², forexample 380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420cm² to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480cm², such as 480 cm² to 500 cm².

It follows that the dimension of the circular base need not be a wholeor counting number, but may also be any decimal number.

The base of the container can comprise an extended base portion at on ormore sides. In one embodiment the extended base portion is placed at thesame side as the handle of the container. The handle and extended baseportion can be casted or moulded in one or more pieces.

The lid of the container can have any shape such as a square, rectangle,triangle, circle, or oval.

In one embodiment the lid of the container is formed as a square e.g.with the dimensions 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1 cm×5cm, 1 cm×6 cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1 cm×15 cm,1 cm×20 cm, 2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2 cm×5 cm, 2cm×6 cm, 2 cm×7 cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2 cm×15 cm, 2cm×20 cm, 3 cm×1 cm, 3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3 cm×5 cm, 3 cm×6cm, 3 cm×7 cm, 3 cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3 cm×15 cm, 3 cm×20 cm,4 cm×1 cm, 4 cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4 cm×5 cm, 4 cm×6 cm, 4 cm×7cm, 4 cm×8 cm, 4 cm×9 cm, 4 cm×10 cm, 4 cm×15 cm, 4 cm×20 cm, 5 cm×1 cm,5 cm×2 cm, 5 cm×3 cm, 5 cm×4 cm, 5 cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8cm, 5 cm×9 cm, 5 cm×10 cm, 5 cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm,6 cm×3 cm, 6 cm×4 cm, 6 cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9cm, 6 cm×10 cm, 6 cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm,7 cm×4 cm, 7 cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7cm×10 cm, 7 cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8cm×4 cm, 8 cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10cm, 8 cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm,9 cm×5 cm, 9 cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9cm×15 cm, 9 cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4 cm, 10cm×5 cm, 10 cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10 cm×10 cm, 10cm×15 cm, 10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3 cm, 11 cm×4 cm,11 cm×5 cm, 11 cm×6 cm, 1 cm×7 cm, 11 cm×8 cm, 11 cm×9 cm, 11 cm×10 cm,11 cm×15 cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2 cm, 12 cm×3 cm, 12 cm×4cm, 12 cm×5 cm, 12 cm×6 cm, 12 cm×7 cm, 12 cm×8 cm, 12 cm×9 cm, 12 cm×10cm, 12 cm×15 cm, 12 cm×20 cm, 13 cm×1 cm, 13 cm×2 cm, 13 cm×3 cm, 13cm×4 cm, 13 cm×5 cm, 13 cm×6 cm, 3 cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13cm×10 cm, 13 cm×15 cm, 13 cm×20 cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm,14 cm×4 cm, 14 cm×5 cm, 14 cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm,14 cm×10 cm, 14 cm×15 cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3cm, 15 cm×4 cm, 15 cm×5 cm, cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm,15 cm×10 cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3cm, 16 cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9cm, 16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm, 17cm×9 cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18 cm×2 cm,18 cm×3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm, 18 cm×8 cm,18 cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19 cm×1 cm, 19 cm×2cm, 19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm, 19 cm×7 cm, 19 cm×8cm, 19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19 cm×20 cm, 20 cm×1 cm, 20cm×2 cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5 cm, 20 cm×6 cm, 20 cm×7 cm, 20cm×8 cm, 20 cm×9 cm, 20 cm×10 cm, 20 cm×15 cm, 20 cm×20 cm, 25 cm×1 cm,25 cm×2 cm, 25 cm×3 cm, 25 cm×4 cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm,25 cm×8 cm, 25 cm×9 cm, 25 cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1cm, 30 cm×2 cm, 30 cm×3 cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7cm, 30 cm×8 cm, 30 cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40cm×1 cm, 40 cm×2 cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40cm×7 cm, 40 cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm,50 cm×1 cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm,50 cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50cm×20 cm.

In one embodiment the lid is formed as a square e.g. with the dimensionsof between 1 cm² to 500 cm², such as 1 cm² to 5 cm², for example 5 cm²to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to 30 cm², suchas 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as 50 cm² to 60cm², for example 60 cm² to 70 cm², such as 70 cm² to 80 cm², for example80 cm² to 90 cm², such as 90 cm² to 100 cm², for example 100 cm² to 110cm², such as 110 cm² to 120 cm², for example 120 cm² to 130 cm², such as130 cm² to 140 cm², for example 140 cm² to 150 cm², such as 150 cm² to160 cm², for example 160 cm² to 170 cm², such as 170 cm² to 180 cm², forexample 180 cm² to 190 cm², such as 190 cm² to 200 cm², for example 200cm² to 210 cm², such as 210 cm² to 220 cm², for example 220 cm² to 230cm², such as 230 cm² to 240 cm², for example 240 cm² to 250 cm², such as250 cm² to 260 cm², for example 260 cm² to 270 cm², such as 270 cm² to280 cm², for example 280 cm² to 290 cm², such as 290 cm² to 300 cm², forexample 300 cm² to 320 cm², such as 320 cm² to 340 cm², for example 340cm² to 360 cm², such as 360 cm² to 380 cm², for example 380 cm² to 400cm², such as 400 cm² to 420 cm², for example 420 cm² to 440 cm², such as440 cm² to 460 cm², for example 460 cm² to 480 cm², such as 480 cm² to500 cm².

It follows that the dimension of the square lid need not be a whole orcounting number, but may also be any decimal number.

In one embodiment the lid of the container is formed as a circle e.g.with a diameter in the range of from 1 cm to 40 cm, such as from 1 cm to2 cm, for example from 2 cm to 4 cm, such as from 4 cm to 6 cm, forexample from 6 cm to 8 cm, such as from 8 cm to 10 cm, for example from10 cm to 12 cm, such as from 12 cm to 14 cm, for example from 14 cm to16 cm, such as from 16 cm to 18 cm, for example from 18 cm to 20 cm,such as from 20 cm to 22 cm, for example from 22 cm to 24 cm, such asfrom 24 cm to 26 cm, for example from 26 cm to 28 cm, such as from 28 cmto 30 cm, for example from 30 cm to 32 cm, such as from 32 cm to 34 cm,for example from 34 cm to 36 cm,

such as from 36 cm to 38 cm, for example from 38 cm to 40 cm.

In one embodiment the lid of the container is formed as a circle e.g.with a diameter of 1 cm, 2, cm, 3, cm, 4, cm, 5, cm, 6 cm, 7 cm, 8 cm, 9cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19cm, 20 cm, 21 cm, 22 cm, 23 cm, 24 cm, 25 cm, 26 cm, 27 cm, 28 cm, 29cm, 30 cm, 31 cm, 32 cm, 33 cm, 34 cm, 35 cm, 36 cm, 37 cm, 38 cm, 39 cmor 40 cm.

In one embodiment the lid is formed as a circle e.g. with the dimensionsof between 1 cm² to 500 cm², such as 1 cm² to 5 cm², for example 5 cm²to 10 cm², such as 10 cm² to 20 cm², for example 20 cm² to 30 cm², suchas 30 cm² to 40 cm², for example 40 cm² to 50 cm², such as 50 cm² to 60cm², for example 60 cm² to 70 cm², such as 70 cm² to 80 cm², for example80 cm² to 90 cm², such as 90 cm² to 100 cm², for example 100 cm² to 110cm², such as 110 cm² to 120 cm², for example 120 cm² to 130 cm², such as130 cm² to 140 cm², for example 140 cm² to 150 cm², such as 150 cm² to160 cm², for example 160 cm² to 170 cm², such as 170 cm² to 180 cm², forexample 180 cm² to 190 cm², such as 190 cm² to 200 cm², for example 200cm² to 210 cm², such as 210 cm² to 220 cm², for example 220 cm² to 230cm², such as 230 cm² to 240 cm², for example 240 cm² to 250 cm², such as250 cm² to 260 cm², for example 260 cm² to 270 cm², such as 270 cm² to280 cm², for example 280 cm² to 290 cm², such as 290 cm² to 300 cm², forexample 300 cm² to 320 cm², such as 320 cm² to 340 cm², for example 340cm² to 360 cm², such as 360 cm² to 380 cm², for example 380 cm² to 400cm², such as 400 cm² to 420 cm², for example 420 cm² to 440 cm², such as440 cm² to 460 cm², for example 460 cm² to 480 cm², such as 480 cm² to500 cm².

It follows that the dimension of the circular lid need not be a whole orcounting number, but may also be any decimal number.

The lid of the container can comprise one or more flaps to facilitateopening of the lid of the container, i.e. for easier handling of the lidwhen opening the container. The flap(s) can have any shape and size thatwould facilitate opening of the lid.

The container can further comprise one or more handles such as 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or more than 10 handles. The one or more handle(s)of the container can have any size and shape that provide easy handlingof the container.

The one or more handles may be associated with the bottom of thecontainer, the one or more sidewall(s) of the container or the base ofthe container.

The one or more handles, the one or more sidewall(s) or the base of thecontainer according to the present invention may comprise one or morerecesses or indentations for improved grip.

In one embodiment the container and/or the lid and/or the base and/orthe bottom and/or the sidewall(s) is made of plastic such as anysuitable plastic known in the art such as medical grade plastic and/or atransparent plastic and/or a non-transparent plastic. The plastic can bea flexible or rigid plastic material with a thickness and strengthproperties which allow the container to be opened by simply tearing thelid from the sealing surface for the lid. Alternatively, a thicker orstronger material may be utilized and the container may be opened bycutting with scissors or otherwise puncturing the container.

In one embodiment the container and/or the lid and/or the base and/orthe bottom and/or the sidewall(s) is made of or comprises plastic suchas one or more types of flexible plastic and/or one or more types oftransparent plastic and/or non-transparent plastic and/or biodegradableplastic.

In one embodiment the container and/or the lid and/or the base and/orthe bottom and/or the sidewall(s) is made of or comprises one or morematerials selected from the group consisting of TECAFORM™ AH MT, CELCON®(Acetal Copolymer), RADEL®, TECASON™ P XRO (Polyphenylsulfone, alsoRadio Opacifer), UDEL® Polysulfone, ULTEM® (Polyetherimide), UHMW LotControlled, LENNITE® UHME-PE, TECANAT™ PC (USP Class VI PolycarbonateRod), ZELUX® GS (Gamma Stabilized Polycarbonate), ACRYLIC (Medical gradeCast Acrylic), TECAMAX™ SRP (Ultra High Performance Thermoplastic),TECAPRO™ MT (Polypropylene Heat Stabilized), TECAPEEK™ MT (USP Class VIcompliant), TECAFORM™ AH SAN, ANTIMICROBIAL filled plastics, TECASON™ PXRO (Biocompatible Radio Opacifer PPSU), TECAPEEK™ CLASSIX, POLYSULFONE®(Medical grade), TECANYL™ (Medical grade Noryl®), TYGON® (Medical gradeTubing), TEXOLON™ Medical Grade PTFE (USP CLASS VI), PROPYLUX HS andHS2, ABS (FDA Approved Medical Grades), TOPAS® (Medical grade), andother Medical Grade/FDA approved plastic products.

In one embodiment the container and/or the lid and/or the base and/orthe bottom and/or the sidewall(s) is made of or comprises one or moretypes of medical grade polymer such as plastic.

Plastic is the general common term for a wide range of synthetic orsemisynthetic organic solid materials suitable for the manufacture ofindustrial products. Plastics are typically polymers of high molecularweight, and may contain other substances to improve performance and/orreduce costs. Types of plastic includes Rubber, Cellulose-basedplastics, Bakelite, Polystyrene, PVC, Nylon, Synthetic rubber. Plasticscan be classified by their chemical structure. Some important groups inthese classifications are the acrylics, polyesters, silicones,polyurethanes, and halogenated plastics. Plastics can also be classifiedby the chemical process used in their synthesis, e.g. as condensation,polyaddition, cross-linking. Other classifications are based onqualities that are relevant for manufacturing or product design.Examples of such classes are the thermoplastic and thermoset, elastomer,structural, biodegradable, electrically conductive. Plastics can also beranked by various physical properties, such as density, tensilestrength, glass transition temperature, resistance to various chemicalproducts, etc. In one embodiment the container and/or the lid and/or thebase is made of or comprises one or more types of plastic mention hereinabove or below.

Common thermoplastics range from 20,000 to 500,000 in molecular mass,while thermosets are assumed to have infinite molecular weight. In oneembodiment the container and/or the lid and/or the base is made of orcomprises one or more types of polymers and/or plastics with a molecularweight in the range from 10,000 to 1,000,000 Da, such as from 10,000 to50,000 Da, for example 50,000 to 100,000 Da, such as from 100,000 to150,000 Da, for example 150,000 to 200,000 Da, such as from 200,000 to250,000 Da, for example 250,000 to 300,000 Da, such as from 300,000 to350,000 Da, for example 350,000 to 400,000 Da, such as from 400,000 to450,000 Da, for example 450,000 to 500,000 Da, such as from 500,000 to550,000 Da, for example 550,000 to 600,000 Da, such as from 600,000 to650,000 Da, for example 650,000 to 700,000 Da, such as from 700,000 to750,000 Da, for example 750,000 to 800,000 Da, such as from 800,000 to850,000 Da, for example 850,000 to 900,000 Da, such as from 900,000 to950,000 Da, for example 950,000 to 1,000,000 Da.

These chains are made up of many repeating molecular units, known as“repeat units”, derived from “monomers”; each polymer chain will haveseveral thousand repeat units. The vast majority of plastics arecomposed of polymers of carbon and hydrogen alone or with oxygen,nitrogen, chlorine, or sulfur in the backbone.

In one embodiment the container and/or the lid and/or the base and/orthe bottom and/or the sidewall(s) is made of or comprises one or morematerials selected from the group consisting of Biodegradable plastic,Bioplastics obtained from biomass e.g. from pea starch or frombiopetroleum, Polypropylene (PP), Polystyrene (PS), High impactpolystyrene (HIPS), Acrylonitrile butadiene styrene (ABS), Polyethyleneterephthalate (PET), Amorphous PET (APET), Polyester (PES), Fibers,textiles, Polyamides (PA), (Nylons), Poly(vinyl chloride) (PVC),Polyurethanes (PU), Polycarbonate (PC), Polyvinylidene chloride (PVDC)(Saran), Polyvinylidene Fluoride (PVDF), Polyethylene (PE), Polymethylmethacrylate (PMMA), Polytetrafluoroethylene (PTFE) (trade name Teflon),Fluorinated ethylene propylene (FEP), Polyetheretherketone (PEEK)(Polyetherketone), Polyetherimide (PEI) (Ultem), Phenolics (PF), (phenolformaldehydes), Perfluoroalkoxy (PFA), Poly(methyl methacrylate) (PMMA),Urea-formaldehyde (UF), Melamine formaldehyde (MF), Polylactic acid andPlastarch material or any mixture thereof.

The container and/or the lid and/or the base and/or the bottom and/orthe sidewall(s) can be made of any suitable material such as plastic,rubber or glass.

The lid and/or the base and/or the bottom and/or the sidewall(s) can beplane, curved, arched upwards or downwards or any other shape.

The sealing surface for the lid can have any size or shape thatfacilitates sealing of the lid to and/or removement of the lid from thecontainer.

In one embodiment the container comprises a reclosable lid such as a lidthat can be resealed by e.g. the glue on the sealing surface for the lidor by a screw, click or snap mechanism. In another embodiment thecontainer comprises a lid that can not be reclosed after opening of thelid.

The container can comprise any type of lid such as a sealing foil, ascrew top, a screw cap, a snap cap, a lid glued to or by any other meansfastened to the sealing surface of the container.

The sealing surface for the lid may be comprised in the upper portion ofthe one or more sidewall(s) or the base.

In one particular embodiment, the lid of the container is peelable (apeel-off lid). It follows that the lid may be made of or comprise apeelable material, such as a polyethylene (PE)-based material, athermoplastic elastomer, a thermoset elastomer, Tyvek, Teslin, paper,foil (plastic foil or metal foil such as alufoil) or any other peelablematerial.

The lid may be reinforced with a coating, such as a synthetic coatingselected from the group consisting of Perfluorooctanoic acid (PFOA),hydrocarbon based petrochemicals, zein or others.

For the purpose of the present invention, peelability will be defined asthe ability to separate two materials in the course of opening a packagewithout compromising the integrity of either of the two. In medicalpackaging, a peelable system provides a controlled, reliable, asepticmeans of opening a package and presenting a device. The sealant layer ofone or both webs is responsible for bonding the two materials together,which is accomplished via the application of heat, pressure or glue.

The force required to pull a seal apart is called its seal strength.Seal strength in a peelable system is controlled by the composition ofeither the heat seal coating or the sealant layer. Typical medicalpackages have a seal strength of 1-3 lb per in. of seal width, asmeasured via a standard test such as ASTM F88-94.

Peelable films are generally based on polybutylene-polyolefin technologyfirst pioneered by Shell in the mid-1970s. The incompatibility of thetwo polymers inhibits the sealant layer from forming a complete bond byreducing the number of available bonding sites. These peelable systemsprovide seal transfer by internal cohesive splitting between thepolyethylene and polybutylene layers because of poor interfacialadhesion, which reduces internal bond strength. This is in contrast toheat-sealed coated (HSC) materials, which undergo the cohesive failurethat occurs when the internal strength of the adhesive is less than thestrength of the bonds between the adhesive and sealed materials.

Peelable films are generally limited to similar-type materials that areprimarily polyethylene (PE) based, and tend to have a narrower sealingwindow and/or a steeper peel-strength slope compared with HSC materials.However, new peelable technologies are being introduced that can provideincreased sealing windows with smaller variations in peel strength overtheir useful range. These new peelable resin systems are being developedto seal to a wide variety of materials, including but not limited toPETG, HIPS, and PVC.

Thermoplastic elastomers (TPE), sometimes referred to as thermoplasticrubbers, are a class of copolymers or a physical mix of polymers(usually a plastic and a rubber) which consist of materials with boththermoplastic and elastomeric properties. The principal differencebetween thermoset elastomers and thermoplastic elastomers is the type ofcrosslinking bond in their structures. There are six generic classes ofTPEs generally considered to exist commercially. They are styrenic blockcopolymers, polyolefin blends, elastomeric alloys, thermoplasticpolyurethanes, thermoplastic copolyester and thermoplastic polyamides.

Paper is thin material mainly used for writing upon, printing upon orpackaging. It is produced by pressing together moist fibers, typicallycellulose pulp derived from wood, rags or grasses, and drying them intoflexible sheets. Synthetic coatings (such as PFOA), hydrocarbon basedpetrochemicals, and zein (corn protein) may be used as a coating forpaper. Also, synthetics such as Tyvek (a brand of flashspun high-densitypolyethylene/olefin fibers) and Teslin have been introduced for medicalpackaging as a more durable material than paper.

The container described in the present invention has the followingadvantages:

-   -   It is very stable—even on uneven surfaces (allows stabile        placement on all possible positions: on sterile field, on mayo        stand, on tray of instruments or on the chest of the patient)        minimizing the risk of spilling    -   It eliminates any need for other mixing bowls/specimen cups    -   It has superior ergonomic handling making handling and        presentation easier and faster from all directions    -   The inner tray notches make it easy to grasp the sponge and thus        not destroying the structure of the matrix material    -   Embossed brand name in tray reduces need to spend additional        time on writing labels for sterile field documentation    -   Dwelling for easier handling of the sponge    -   Bevelled edges to ensure that e.g. the saline volume stays        inside the tray thus not dripping onto the sterile field    -   Bevelled edges or other indication as a guiding tool for maximum        amount of moisture to add

In one embodiment addition of liquid to the container results in thatthe liquid/moisture is evenly distributed throughout the matrixmaterial. The even distribution of liquid/moisture can be obtained bymanual massage of the matrix material (e.g. with the fingers).

In one embodiment the liquid added to the container does not cover thematrix material before and/or after the absorption of liquid into thematrix material. In one embodiment the liquid added to the matrixmaterial in the container reaches from ½-⅔ of the height from the bottomof the inner tray to the mark for maximum filling of the tray beforeabsorption of liquid into the matrix material.

In another embodiment the liquid added to the matrix material in thecontainer reaches from 10% to 100% of the height from the bottom of theinner tray to the mark for maximum filling of the tray before absorptionof liquid into the matrix material, such as from 10% to 12%, for examplefrom 12% to 14%, such as from 14% to 16%, for example from 16% to 18%,such as from 18% to 20%, for example from 20% to 22%, such as from 22%to 24%, for example from 24% to 26%, such as from 26% to 28%, forexample from 28% to 30%, such as from 30% to 32%, for example from 32%to 34%, such as from 34% to 36%, for example from 36% to 38%, such asfrom 38% to 40%, for example from 40% to 42%, such as from 42% to 44%,for example from 44% to 46%, such as from 46% to 48%, for example from48% to 50%, such as from 50% to 52%, for example from 52% to 54%, suchas from 54% to 56%, for example from 56% to 58%, such as from 58% to60%, for example from 60% to 62%, such as from 62% to 64%, for examplefrom 64% to 66%, such as from 66% to 68%, for example from 68% to 70%,such as from 70% to 72%, for example from 72% to 74%, such as from 74%to 76%, for example from 76% to 78%, such as from 78% to 80%, forexample from 80% to 82%, such as from 82% to 84%, for example from 84%to 86%, such as from 86% to 88%, for example from 88% to 90%, such asfrom 90% to 92%, for example from 92% to 94%, such as from 94% to 96%,for example from 96% to 98%, such as from 98% to 100% of the height fromthe bottom of the inner tray to the mark for maximum filling.

In another embodiment the liquid added to the matrix material in thecontainer reaches from 10% to 100% of the height from the bottom of theinner tray to the mark for maximum filling of the tray after absorptionof liquid into the matrix material, such as from 10% to 12%, for examplefrom 12% to 14%, such as from 14% to 16%, for example from 16% to 18%,such as from 18% to 20%, for example from 20% to 22%, such as from 22%to 24%, for example from 24% to 26%, such as from 26% to 28%, forexample from 28% to 30%, such as from 30% to 32%, for example from 32%to 34%, such as from 34% to 36%, for example from 36% to 38%, such asfrom 38% to 40%, for example from 40% to 42%, such as from 42% to 44%,for example from 44% to 46%, such as from 46% to 48%, for example from48% to 50%, such as from 50% to 52%, for example from 52% to 54%, suchas from 54% to 56%, for example from 56% to 58%, such as from 58% to60%, for example from 60% to 62%, such as from 62% to 64%, for examplefrom 64% to 66%, such as from 66% to 68%, for example from 68% to 70%,such as from 70% to 72%, for example from 72% to 74%, such as from 74%to 76%, for example from 76% to 78%, such as from 78% to 80%, forexample from 80% to 82%, such as from 82% to 84%, for example from 84%to 86%, such as from 86% to 88%, for example from 88% to 90%, such asfrom 90% to 92%, for example from 92% to 94%, such as from 94% to 96%,for example from 96% to 98%, such as from 98% to 100% of the height fromthe bottom of the inner tray to the mark for maximum filling.

The mark for maximum filling of the inner tray helps to ensure that toomuch liquid can not be added to the matrix material in the container. Iftoo much liquid has been added to the matrix material in the container,the liquid that remains in the tray after absorption of liquid into thematrix material will comprise the pharmaceutical composition from thematrix material (e.g. Thrombin).

One advantage of using a matrix material with added liquid is that thematrix material becomes more mouldable and softer than a dry matrixmaterial.

In one embodiment the pharmaceutical composition such as Thrombin isonly applied e.g. by printing on one or more of the surfaces of thematrix material. In another embodiment the pharmaceutical compositionsuch as Thrombin is applied throughout the matrix materiel. However,after liquid has been added to the matrix material and after absorptionof liquid into the matrix material has occurred the pharmaceuticalcomposition such as Thrombin will often be distributed throughout thematrix material.

In one preferred embodiment the container with the matrix materialaccording to the present invention has the shape and size shown in FIG.4—termed Teacup100. Teacup100 is made for addition of a volume of liquidof maximum 20 mL.

In one preferred embodiment the container with the matrix materialaccording to the present invention has the shape and size shown in FIG.5—termed Teacup50. Teacup50 is made for addition of a volume of liquidof maximum 10 mL.

In one preferred embodiment the container with the matrix materialaccording to the present invention has the shape and size shown in FIG.6—termed Teacup12-7. Teacup12-7 is made for addition of a volume ofliquid of maximum 2 mL.

The liquid to be added to the container used for wetting the matrixmaterial may be selected from the group consisting of an aqueoussolution; a saline solution such as NaCl 0.9% (normal saline);medical-grade water; water for injection; water for irrigation; salinefor injection; saline for irrigation; an antibiotic solution comprisingan antiobiotic selected from those listed in Table 5 above includingpenicillins, cephalosporins, tetracyclines, ampiciflin, aureothicin,bacitracin, chloramphenicol, cycloserine, erythromycin, gentamicin,gramacidins, kanamycins, neomycins, streptomycins, tobramycin, andvancomycin; an anaesthetic solution comprising a local anaestheticselected from Lidocaine/prilocalne (EMLA), Articaine, Bupivacaine,Carticaine, Cinchocaine/Dibucaine, Etidocaine, Levobupivacaine,Lidocaine/Lignocaine, Mepivacaine, Piperocaine, Prilocalne, Ropivacaine,Trimecaine, Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine,Dimethocaine/Larocaine, Propoxycaine, Procaine/Novocaine, Proparacaine,Tetracaine/Amethocaine; a solution comprising adrenaline (epinephrine),and others.

A Kit of Parts

The present invention also relates to a kit of parts and use of said kitof parts. In one embodiment the kit of parts comprises a matrix materialas described elsewhere herein such as a matrix material printed with oneor more pharmaceutical compositions or a matrix material comprisingthrombin. In another embodiment the kit of parts comprises the containerfor storage of a matrix material as described herein above.

The kit of parts can be used to apply a matrix material e.g. a matrixmaterial comprising thrombin such as a matrix material with thrombinprinted onto one or more surfaces of the matrix material onto an injuredportion of a mammalian body such a wound on a human being.

The kit of parts can be used to treat a wound, to accelerate or promotehemostasis or accelerate or promote wound healing in an individual inneed thereof. The kit of parts comprising the container and a matrixmaterial comprising a pharmaceutical composition such as thrombinprovides a sterile storage of said matrix material. The appropriatemedical personnel decide which pharmaceutical composition is appropriatefor the wound in question.

The container is opened either completely or partly by removement of thelid e.g. by cutting, peeling or tearing of the lid from the lid sealingsurface. The matrix material can then optionally be removed and cut intopieces of relevant size(s) and be placed in the container again. Apredetermined volume of liquid/moisture such as water or saline is addedto the container e.g. up to the mark on the one or more sidewalls. Afterabsorption of liquid into the matrix material, the matrix material isplaced on the wound. Alternatively, the matrix material can be cut intopieces of relevant sizes after liquid has been added to the matrixmaterial.

Combination Therapy

The fluid or liquid composition according to the present invention maycontain substances selected form the group consisting of hemostatic oranti-fibrinolytic agents, wound healing agents, adhesive agents andsurfactants, as disclosed above.

In a preferred embodiment of the invention, the pharmaceuticalcomposition according to the present invention may comprise more thanone agent, selected from tables 1 to 4.

Thus, the composition may comprise more than 1, such as 2, for example3, such as 4, for example 5, such as 6, for example 7, such as 8different agents selected from tables 1 to 4. Table 1 comprises examplesof hemostatic or anti-fibrinolytic agents; table 2 comprises examples ofwound healing agents; table 3 comprises examples of adhesive agents andtable 4 comprises examples of surfactants.

In one embodiment, the composition comprises at least 1, such as 2, forexample 3, such as 4, for example 5, such as 6, for example 7, such as 8different agents selected from table 1, further comprising at least 1,such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 2.

In another embodiment, the composition comprises at least 1, such as 2,for example 3, such as 4, for example 5, such as 6, for example 7, suchas 8 different agents selected from table 1, further comprising at least1, such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 3.

In yet another embodiment, the composition comprises at least 1, such as2, for example 3, such as 4, for example 5, such as 6, for example 7,such as 8 different agents selected from table 1, further comprising atleast 1, such as 2, for example 3, such as 4, for example 5, such as 6,for example 7, such as 8 different agents selected from table 4.

In one embodiment, the composition comprises at least 1, such as 2, forexample 3, such as 4, for example 5, such as 6, for example 7, such as 8different agents selected from table 2, further comprising at least 1,such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 3.

In another embodiment, the composition comprises at least 1, such as 2,for example 3, such as 4, for example 5, such as 6, for example 7, suchas 8 different agents selected from table 2, further comprising at least1, such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 4.

In one embodiment, the composition comprises at least 1, such as 2, forexample 3, such as 4, for example 5, such as 6, for example 7, such as 8different agents selected from table 1, further comprising at least 1,such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 2, stillfurther comprising at least 1, such as 2, for example 3, such as 4, forexample 5, such as 6, for example 7, such as 8 different agents selectedfrom table 3.

In another embodiment, the composition comprises at least 1, such as 2,for example 3, such as 4, for example 5, such as 6, for example 7, suchas 8 different agents selected from table 1, further comprising at least1, such as 2, for example 3, such as 4, for example 5, such as 6, forexample 7, such as 8 different agents selected from table 2, stillfurther comprising at least 1, such as 2, for example 3, such as 4, forexample 5, such as 6, for example 7, such as 8 different agents selectedfrom table 4.

In yet another embodiment, the composition comprises at least 1, such as2, for example 3, such as 4, for example 5, such as 6, for example 7,such as 8 different agents selected from table 1, further comprising atleast 1, such as 2, for example 3, such as 4, for example 5, such as 6,for example 7, such as 8 different agents selected from table 2, furthercomprising at least 1, such as 2, for example 3, such as 4, for example5, such as 6, for example 7, such as 8 different agents selected fromtable 3, and also further comprising at least 1, such as 2, for example3, such as 4, for example 5, such as 6, for example 7, such as 8different agents selected from table 4.

According to the preferred embodiments cited here above, agents may beadministered onto the matrix of the device of the invention via inkjetprinting, by printing a pharmaceutical composition containing agentsfrom either 1, 2, 3 or 4 classes of agents, as cited in tables 1 to 4.

EXAMPLES

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

Example 1 Determination of the Reconformation Rate of Gelatin-BasedSponges

The purpose of this method is to determine the reconformation rate of agelatin-based sponge. The method comprises soaking the sponge, andsubsequently squeezing it. The appearance of the native shape of thesponge is monitored as a function of time, and the time that lapsesuntil the sponge has reached its native shape is termed thereconformation time.

The method comprises the following steps:

1. Cut a suitable piece of absorbable gelatin-based sponge,approximately 1×1 cm, and thoroughly soak it in water at roomtemperature.2. Remove the sample from the water, and squeeze it until it is flat andno more air bubbles or drops of water can be pressed out.3. Place the sample in a beaker filled with water at room temperatureand measure the time (in seconds) until the sample has gained its formersize and shape.4. Repeat the test twice and report the result as the average of threedeterminations.

Example 2

This gives an example of a possible print medium or composition forprinting onto a surface of a matrix. In this example, the bioactiveagent comprised in the pharmaceutical composition is thrombin, and thematrix is a collagen-based sponge.

Print media: sterile MQ-water, sterile saline or another appropriatesterile aqueous solvent is adjusted with a suitable biocompatibleviscosity enhancer, such as gelatin, to 10 cps. Thrombin isreconstituted to a suitable concentration in the media. Thisconcentration should be adjusted so that the final concentration ofthrombin yields 30 IU/cm² on the surface of the matrix to be imprinted.The pH is kept within physiological ranges, and the temperature is heldat ambient temperature (around 25° C.). If desired, a suitablesurfactant may be added to the medium.

The matrix chosen is in one embodiment a gelatin-based sponge, such asthe commercially available Spongostan®, Surgifoam® or Surgiflo®(Ferrosan A/S). The sponge may be cut into a suitable form and shape.

The accuracy of the printing head and the control of the printing headmust be very high, since this controls the amount that is printed andthus the dosage of thrombin on the fabricated sponge. This is importanteven at high rates of production (such as 60 sponges per minute).

Example 3 Hemostatic Effect for a Matrix Printed with Thrombin

A pig model has been used to test the effect on hemostasis of differentamounts of thrombin printed onto a matrix (Surgifoam™; Johnson andJonhson). Wet and dry application of the thrombin matrix is compared.For dry applications thrombin was when indicated in the diagram printedonto the matrix for low concentrations of thrombin (20, 10 or 5 IU/cm²).A matrix printed with thrombin used for dry applications has asurprisingly effective hemostatic effect (measured in time forhemostasis) at low concentrations of thrombin (see FIG. 8).

FIG. 8 shows that dry application of 20 IU/cm² printed thrombin resultsin faster hemostasis than wet application of the same amount ofthrombin. Furthermore, dry application of 10 IU/cm² printed thrombinresults in similar or even faster hemostatis than wet application of 200IU/cm² thrombin.

The present invention relates in one embodiment to a matrix such asSurgifoam™ printed with an amount of thrombin resulting in a time ofhemostasis after dry application (measured by the assay described above)below 200 seconds, such as below 190 seconds, for example below 180seconds, such as below 170 seconds, for example below 160 seconds, suchas below 150 seconds, for example below 140 seconds, such as below 130seconds, for example below 120 seconds, such as below 110 seconds, forexample below 100 seconds, such as below 90 seconds, for example below80 seconds, such as below 70 seconds, for example below 60 seconds, suchas below 50 seconds, for example below 48 seconds, such as below 46seconds, for example below 44 seconds, such as below 42 seconds, forexample below 40 seconds, such as below 38 seconds, for example below 36seconds, such as below 34 seconds, for example below 32 seconds, such asbelow 30 seconds, for example below 28 seconds, such as below 26seconds, for example below 24 seconds, such as below 22 seconds, forexample below 20 seconds, such as below 18 seconds, for example below 16seconds, such as below 14 seconds, for example below 12 seconds, such asbelow 10 seconds, for example below 8 seconds, such as below 6 seconds,for example below 4 seconds, such as below 2 seconds, for example below1 second.

Example 4 Use of a Container with a Matrix Material in an Operating Room

This example describes one example of use of a container with a matrixmaterial in an operating room.

A person such as a scrub tech/RN places the container/tray on a sterilefield, uses the handle to hold the container/tray while removing the lide.g. a tyvek lid. In one embodiment everything on the sterile field islabelled to minimize any mistakes. The person such as the scrub tech/RNchecks that the product name has been embossed on the container/traythus giving confidence that no additional labeling needs to be done. Themixing preparation on the lid serves as a guiding to remind the personhow to mix the product correctly. The scrub tech/RN uses the notches(inside dwellings) to take up the matrix material such as a sponge fromthe container/tray with the fingers, tweezers, forceps or an alternativedevice. The scrub tech/RN cuts the matrix material such as a sponge intothe container/tray omitting the need for a bowl. When matrix materialpieces have been cut, the scrub tech/RN applies the appropriate amountof liquid, such as sodium chloride, such as sodium chloride 0.9%, on topof the matrix material/sponge pieces. The Scrub tech may use for examplefingers or a pair of forceps to poke the liquid/sodium chloride/sodiumchloride 0.9% into the matrix materials/sponge pieces. When this isdone, the scrub tech/RN optionally uses the handle on the tray to placethe tray until needed by e.g. the surgeon: the tray may e.g. be placedon the sterile field, back table (sterile), on the mayo stand, on thechest of the patient (e.g. on sterile cover). The scrub tech/RN may holdthe handle when presenting the product to the surgeon and while thesurgeon picks up the sponges that he wants from the tray. Alternatively,the tray may be placed on e.g. the mayo stand and the scrub tech/RNgives the surgeon individual matrix materials/sponge pieces on a pairforceps. If surgeon desires to use soaked e.g. saline soaked patties orcottonoids on top of the matrix material/sponge pieces for compression,these can be placed on the flat part of the tray.

Example 5

This example describes one example of printing a fluid, pharmaceuticalcomposition with thrombin onto a matrix material; wherein the ratio ofdroplet volume, the distance between droplets deposited on the surfaceof the matrix material and the concentration of thrombin is fixed toachieve a uniform distribution pattern.

In this example, the bioactive agent comprised in the fluid or liquidcomposition is thrombin, and the matrix is a gelatin-based sponge.

Print media: sterile MQ-water, sterile saline or another appropriatesterile aqueous solvent is adjusted with a suitable biocompatibleviscosity enhancer, such as gelatin, to 10 cps. Thrombin isreconstituted to a concentration of 8-10,000 IU/ml in the media. The pHis kept within physiological ranges, and the temperature is held atambient temperature (around 25° C.). If desired, a suitable surfactantmay be added to the medium.

A fluid or liquid composition comprising thrombin at a concentration of8-10,000 IU/ml is filled in a reservoir connected to a print head, suchas a Spectra® Galaxy Printhead 256/80 HM piezoelectric inkjet printhead.The distance between the printhead and the gelatin-sponge is adjusted to2 mm.

Printing is initiated and droplets of essentially 80 μL in size areexpelled from the 256 nozzles of the print head at a velocity of 8m/sec, such that the distance between any two droplets is 254 microns.The jet straightness is 5 mrad (0.29°).

Items

-   1. A matrix material comprising a surface and a plurality of open    and interconnected cells, wherein the surface of said matrix    comprises at least one pharmaceutical composition printed onto said    surface in individual and discrete locations.-   2. The matrix material according to item 1, wherein the matrix    comprises one or more polymers.-   3. The matrix material according to item 2, wherein said polymers    are cross-linked.-   4. The matrix material according to item 2, wherein said polymers    are not cross-linked.-   5. The matrix material according to item 2, wherein said polymers    are selected from the group consisting of collagen, gelatin,    polyurethane, polysiloxanes (silicone), hydrogels, polyacrylamides,    chitosan, sodium polyacrylate, agarose, alginates, xanthan gum, guar    gum, arabic gum, agar gum, Locust Bean gum, Carrageenan gum, Xanthan    gum, Karaya gum, tragacanth gum, Ghatti gum, Furcelleran gum,    chitin, cellulose, methylcellulose, carboxymethyl cellulose,    hydroxymethyl cellulose, hydroxypropyl methylcellulose,    hydroxypropyl cellulose, hyaluronic acid, pectin, starch, glycogen,    pentosans, polyoxyethylene, polyAMPS    (poly(2-acrylamido-2-methyl-1-propanesulfonic acid),    polyvinylpyrrolidone, polyvinyl alcohol, polyglycolic acid,    polyacetic acid, acrylate polymers, polyhydroxyalkyl acrylates,    methacrylates, polyvinyl lactams, polyvinyl alcohols,    polyoxyalkylenes, polyacrylamides, polyacrylic acid, polystyrene    sulfonates, synthetic hydrocolloids such as N-vinyl-2-pyrrolidone,    5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone,    3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone,    3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone,    4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam,    N-vinyl-2-caprolactam, hydroxyalkyl acrylates and methacrylates,    (such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate,    2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate,    2,3-dihydroxypropyl methacrylate), acrylic acid, methacrylic acid,    tertiary amino-methacrylimide, (e.g. trimethylamino-methacrylimide),    crotonic acid, pyridine, water soluble amides, (such as    N-(hydroxymethyl)acrylamide and -methacrylamide,    N-(3-hydroxpropyl)acrylamide, N-(2-hydroxyethyl)methacrylamide,    N-(1,1-dimethyl-3-oxabutypacrylamide    N-[2-(dimethylamine)ethyl]acrylamide and -methacrylamide,    N-[3-(dimethylamino)-2-hydroxylpropyl]methacrylamide, and    N-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide);    water-soluble hydrazine derivatives, (such as trialkylamine    methacrylimide, and dimethyl-(2-hydroxypropyl)amine methacrylimide);    mono-olefinic sulfonic acids and their salts, (such as sodium    ethylene sulfonate, sodium styrene sulfonate,    2-acrylamideo-2-methylpropanesulfonic acid), 1-vinyl-imidazole,    1-vinyl-indole, 2-vinyl imidazole, 4(5)-vinyl-imidazole,    2-vinyl-1-methyl-imidazole, 5-vinyl-pyrazoline,    3-methyl-5-isopropenyl-pyrazole, 5-methylene-hydantoin,    3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone,    3-methacrylyl-5-methyl-2-oxazolidone,    3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinyl-pyridine,    5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1-oxide,    3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and    4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine,    4-acrylyl-morpholine, Oxidized Regenerated Cellulose (ORC),    polylactic-co-glycolic acid) (PLGA), Polylactic acid (PLA),    Extracellular matrix (ECM), and mixtures thereof-   6. The matrix material according to item 2, wherein the polymers    originates from an animal source such as porcine, bovine or fish    sources.-   7. The matrix material according to item 2, wherein the polymers are    synthetically made i.e. by recombinant means.-   8. The matrix material according to item 2, wherein the polymers are    selected from collagen and gelatin.-   9. The matrix material according to item 2, wherein the polymers    comprise gelatin.-   10. The matrix material according to item 2, wherein the polymers    comprise collagen.-   11. The matrix material according to item 1, wherein the    interconnected open cells form pores having a diameter of from about    0.1 mm to about 5.0 mm.-   12. The matrix material according to item 1, wherein the matrix has    the dimensions (length, width and height) of less than 15 cm long,    less than 10 cm wide and less than 2 cm high.-   13. The matrix material according to item 1, wherein the matrix is a    shape selected from the group consisting of square form, circular    form, rectangular form, cubic form, cylinder form, spherical or    pyramid-shaped.-   14. The matrix material according to item 1, wherein the matrix has    a colour selected from the group consisting of red, pink, yellow,    blue, green, white, black, brown, purple, orange, grey and    turquoise.-   15. The matrix material according to item 1, wherein the matrix    material has a reconformation rate of no more than 10 seconds, such    as no more than 9 seconds, for example no more than 8 seconds, such    as no more than 7 seconds, for example no more than 6 seconds, such    as no more than 5 seconds, for example no more than 4 seconds, such    as no more than 3 seconds, for example no more than 3 seconds, such    as no more than 1 second.-   16. The matrix material according to item 1, wherein the matrix    material has a pore size with a normal distribution around 0.1-1.0    mm.-   17. The matrix material according to item 1, wherein the matrix    material has a pore size of less than 10 mm, such as less than 9 mm,    for example less than 8 mm, such as less than 7 mm, for example less    than 6 mm, such as less than 5 mm, for example less than 4 mm, such    as less than 3 mm, for example less than 2.9 mm, such as less than    2.8 mm, for example less than 2.7 mm, such as less than 2.6 mm, for    example less than 2.5 mm, such as less than 2.4 mm, for example less    than 2.3 mm, such as less than 2.2 mm, for example less than 2.1 mm,    such as less than 2 mm, for example less than 1.9 mm, such as less    than 1.8 mm, for example less than 1.7 mm, such as less than 1.6 mm,    for example less than 1.5 mm, such as less than 1.4 mm, for example    less than 1.3 mm, such as less than 1.2 mm, for example less than    1.1 mm, such as less than 1.0 mm, for example less than 0.9 mm, such    as less than 0.8 mm, for example less than 0.7 mm, such as less than    0.6 mm, for example less than 0.5 mm, such as less than 0.4 mm, for    example less than 0.3 mm, such as less than 0.2 mm, for example less    than 0.1 mm, such as less than 0.05, for example less than 0.01 mm.-   18. The matrix material according to item 1, wherein the matrix    material has a pore size in the range of 0.01-0.1 mm, such as    0.1-0.2 mm, for example 0.2-0.3 mm, such as 0.3-0.4 mm, for example    0.4-0.5 mm, such as 0.5-0.6 mm, for example 0.6-0.7 mm, such as    0.7-0.8 mm, for example 0.8-0.9 mm, such as 0.9-1 mm, for example    1-1.1 mm, such as 1.1-1.2 mm, for example 1.2-1.3 mm, such as    1.3-1.4 mm, for example 1.4-1.5 mm, such as 1.5-1.6 mm, for example    1.6-1.7 mm, such as 1.7-1.8 mm, for example 1.8-1.9 mm, such as    2-2.1 mm, for example 2.1-2.2 mm, such as 2.2-2.3 mm, for example    2.3-2.4 mm, such as 2.4-2.5 mm, for example 2.5-2.6 mm, such as    2.6-2.7 mm, for example 2.7-2.8 mm, such as 2.8-2.9 mm, for example    2.9-3 mm, such as 3-4 mm, for example 4-5 mm, such as 5-6 mm, for    example 6-7 mm, such as 7-8 mm, for example 8-9 mm, such as 9-10 mm.-   19. The matrix material according to item 1, wherein the matrix    material has a modulus in the range of 0.1-50 GPa, such as 0.1-1,    for example 1-2, such as 2-3, such as 3-4, for example 4-5, such as    5-6, for example, 6-7, such as 7-8, for example 8-9, such as 9-10,    for example 10-20, such as 20-30, for example 30-40, such as 40-50    GPa.-   20. The matrix material according to item 1, wherein the surface of    the matrix contains less than 100 IU/cm², such as less than 95, for    example less than 90, such as 85, for example less than 80, such as    less than 75, for example less than 70, such as 65, for example less    than 60, such as less than 55, for example less than 50, such as 45,    for example less than 40, such as less than 35, for example less    than 30, such as 25, for example less than 20, such as less than 15,    for example less than 10, such as 5, for example less than 1 IU/cm²    of the pharmaceutical composition.-   21. The matrix material according to item 1, wherein the surface of    the matrix contains between 1-5 IU/cm², such as 5-10, for example    10-15, such as 15-20, for example 20-25, such as 25-30, for example    30-35, such as 35-40, for example 40-45, such as 45-50, for example    50-55, such as 55-60, for example 60-65, such as 65-70, for example    70-75, such as 75-80, for example 80-85, such as 85-90, for example    90-95, such as 95-100 IU/cm² of the pharmaceutical composition.-   22. The matrix material according to item 1, wherein the matrix    material is a sponge.-   23. The matrix material according to item 22, wherein the sponge is    a gelatin or collagen sponge.-   24. The matrix material according to item 23, wherein the gelatin or    collagen sponge is selected from the group consisting of Spongostan,    Surgifoam, Surgiflo (all Ferrosan A/S), Collastat (Kendall Co.),    Avitene (Avicon Inc.), Surgicel, Surgifoam (both Johnson & Johnson)    and Gelfoam (Phizer).-   25. The matrix material according to item 1, wherein the matrix    material is a patch.-   26. The matrix material according to item 1, wherein the matrix    material is a swab.-   27. The matrix material according to item 1, wherein the matrix    material is a bandage.-   28. The matrix material according to item 1, wherein the matrix    material is a wound dressing.-   29. The matrix material according to item 1, wherein the matrix    material is a tissue dressing.-   30. The matrix material according to item 1, wherein the matrix    material is sterile.-   31. The matrix material according to item 1, wherein the matrix    material is sterile and contained in a sterile, pre-packaged,    ready-to-use container.-   32. The matrix material according to item 1, wherein the matrix    material is sterilized.-   33. The matrix material according to item 1, wherein the matrix    material is sterilized by application of heat.-   34. The matrix material according to item 1, wherein the matrix    material is sterilized by application of one or more chemicals.-   35. The matrix material according to item 1, wherein the matrix    material is sterilized by application of high pressure.-   36. The matrix material according to item 1, wherein the matrix    material is sterilized by application of filtration.-   37. The matrix material according to item 1, wherein the matrix    material is sterilized by application of autoclaving.-   38. The matrix material according to item 1, wherein the matrix    material is sterilized by application of radiation sterilization    such as sterilization using X-rays, gamma rays, UV light and/or    subatomic particles.-   39. The matrix material according to item 1, wherein the matrix    material is sterilized by application of chemical sterilization    include use of one or more of the chemicals selected from the group    consisting of ethylene oxide gas, ozone, chlorine bleach,    glutaraldehyde, formaldehyde, ortho phthalaldehyde, hydrogen    peroxide and peracetic acid.-   40. The matrix material according to item 30, wherein the matrix    material is contained in a sterile container and separated from an    external, non-sterile environment.-   41. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s).-   42. The pharmaceutical composition according to item 41, wherein    said bioactive agent is of a concentration in the range of 1 IU/ml    to 1,000,000 IU/ml; such as 1-10 IU/ml, for example 10-50 IU/ml,    such as 50-100 IU/ml, for example 100-150 IU/ml, such as 150-200    IU/ml, for example 200-250 IU/ml, such as 250-300 IU/ml, for example    300-350 IU/ml, such as 350-400 IU/ml, for example 400-450 IU/ml,    such as 450-500 IU/ml, for example 500-750 IU/ml, such as 750-1000    IU/ml, for example 1000-1500 IU/ml, such as 1500-2000 IU/ml, for    example 2000-2500 IU/ml, such as 2500-3000 IU/ml, for example    3000-3500 IU/ml, such as 3500-4000 IU/ml, for example 4000-4500    IU/ml, such as 4500-5000 IU/ml, for example 5000-5500 IU/ml, such as    5500-6000 IU/ml, for example 6000-6500 IU/ml, such as 6500-7000    IU/ml, for example 7000-7500 IU/ml, such as 7500-8000 IU/ml, for    example 8000-8500 IU/ml, such as 8500-9000 IU/ml, for example    9000-9500 IU/ml, such as 9500-10,000 IU/ml, for example    10,000-11,000 IU/ml, such as 11,000-12,000 IU/ml, for example    12,000-13,000 IU/ml, such as 13,000-14,000 IU/ml, for example    14,000-15,000 IU/ml, such as 15,000-16,000 IU/ml, for example    16,000-17,000 IU/ml, such as 17,000-18,000 IU/ml, for example    18,000-19,000 IU/ml, such as 19,000-20,000 IU/ml, for example    20,000-25,000 IU/ml, such as 25,000-30,000 IU/ml, for example    30,000-35,000 IU/ml, such as 35,000-40,000 IU/ml, for example    40,000-45,000 IU/ml, such as 45,000-50,000 IU/ml, for example    50,000-55,000 IU/ml, such as 55,000-60,000 IU/ml, for example    60,000-65,000 IU/ml, such as 65,000-70,000 IU/ml, for example    70,000-75,000 IU/ml, such as 75,000-80,000 IU/ml, for example    80,000-85,000 IU/ml, such as 85,000-90,000 IU/ml, for example    90,000-95,000 IU/ml, such as 95,000-100,000 IU/ml, for example    100,000-150,000 IU/ml, such as 150,000-200,000 IU/ml, for example    200,000-250,000 IU/ml, such as 250,000-300,000 IU/ml, for example    300,000-350,000 IU/ml, such as 350,000-400,000 IU/ml, for example    400,000-450,000 IU/ml, such as 450,000-500,000 IU/ml, for example    500,000-550,000 IU/ml, such as 550,000-600,000 IU/ml, for example    600,000-650,000 IU/ml, such as 650,000-700,000 IU/ml, for example    700,000-750,000 IU/ml, such as 750,000-800,000 IU/ml, for example    800,000-850,000 IU/ml, such as 850,000-900,000 IU/ml, for example    900,000-950,000 IU/ml, such as 950,000-1,000,000 IU/ml.-   43. The pharmaceutical composition according to item 41, wherein    said bioactive agent is of a concentration in the range of 1 ng/ml    to 1,000,000 mg/ml; such as 1-10 ng/ml, for example 10-100 ng/ml,    such as 100-200 ng/ml, for example 300-400 ng/ml, such as 400-500    ng/ml, for example 500-600 ng/ml, such as 600-700 ng/ml, for example    700-800 ng/ml, such as 800-900 ng/ml, for example 900-1000 ng/ml,    such as 1-10 ug/ml, for example 10-100 ug/ml, such as 100-200 ug/ml,    for example 200-300 ug/ml, such as 300-400 ug/ml, for example    400-500 ug/ml, such as 500-600 ug/ml, for example 600-700 ug/ml,    such as 700-800 ug/ml, for example 800-900 ug/ml, such as 900-1000    ug/ml, for example 1-10 mg/ml, such as 10-100 mg/ml, for example    100-200 mg/ml, such as 200-300 mg/ml, for example 300-400 mg/ml,    such as 400-500 mg/ml, for example 500-600 mg/ml, such as 600-700    mg/ml, for example 700-800 mg/ml, such as 800-900 mg/ml, for example    900-1000 mg/ml, such as 1000-2000 mg/ml, for example 2000-3000    mg/ml, such as 3000-4000 mg/ml, for example 4000-5000 mg/ml, such as    5000-6000 mg/ml, for example 6000-7000 mg/ml, such as 7000-8000    mg/ml, for example 8000-9000 mg/ml, such as 9000-10,000 mg/ml, for    example 10,000-20,000 mg/ml, such as 20,000-30,000 mg/ml, for    example 30,000-40,000 mg/ml, such as 40,000-50,000 mg/ml, for    example 50,000-60,000 mg/ml, such as 60,000-70,000 mg/ml, for    example 70,000-80,000 mg/ml, such as 80,000-90,000 mg/ml, for    example 90,000-100,000 mg/ml, such as 100,000-200,000 mg/ml, for    example 200,000-300,000 mg/ml, such as 300,000-400,000 mg/ml, for    example 400,000-500,000 mg/ml, such as 500,000-600,000 mg/ml, for    example 600,000-700,000 mg/ml, such as 700,000-800,000 mg/ml, for    example 800,000-900,000 mg/ml, such as 900,000-1,000,000 mg/ml.-   44. The matrix material according to item 41, wherein the    concentration of the bioactive agent of any two droplets expelled    from a print head vary less that 10%, such as less than 8%, for    example less than 6%, such as less than 4%, for example less than    2%, such as less than 1%.-   45. The matrix material according to item 44, wherein the    concentration of the bioactive agent of any two droplets is    essentially identical.-   46. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates hemostasis.-   47. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates wound healing.-   48. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates wound healing by inhibition of one or more    infections of the wound.-   49. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises one or more anti-fibrinolytic agents.-   50. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises one or more pro-coagulants.-   51. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates platelets.-   52. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulate formation of a hemostatic plug.-   53. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates one or more coagulation factors.-   54. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    selected from the group consisting of endothelium Tissue Factor    (TF), Factor VII, TF-Factor VIIa, Factor IX, Factor X, thrombin,    Factor XIa, plasmin, Factor XII, Factor Xa, TFPI, Factor Va,    prothrombinase complex, prothrombin, Factor V, Factor XI, Factor    VIII, vWF, Factor VIIIa, Factor IXa and the tenase complex.-   55. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the formation of fibrin strands.-   56. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates platelate aggregation.-   57. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises thrombin.-   58. The matrix material according to items 1 and 57, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises fibrinogen.-   59. The matrix material according to items 1 and 57, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor XIII and/or XIIIa.-   60. The matrix material according to items 1 and 57, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises tranexamic acid.-   61. The matrix material according to items 1 and 57, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Willebrand factor (vWF).-   62. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the contact activation pathway.-   63. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the tissue factor pathway.-   64. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates fibrin formation.-   65. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates fibrin cross-linking.-   66. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor VIII.-   67. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor V.-   68. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor XIII.-   69. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor VII.-   70. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which stimulates the coagulation cascade.-   71. The matrix material according to item 1, wherein the    pharmaceutical composition comprises thrombin.-   72. The matrix material according to item 71, wherein the matrix    contains less than 300 IU thrombin per square cm (cm²) surface area,    such as less than 290, for example less than 280, such as 270, for    example less than 260, such as less than 250, for example less than    240, such as 230, for example less than 220, such as less than 210,    for example less than 200, such as 190, for example less than 180,    such as less than 170, for example less than 160, such as 150, for    example less than 140, such as less than 130, for example less than    120, such as 110, for example less than 100 IU/cm², such as less    than 95, for example less than 90, such as 85, for example less than    80, such as less than 75, for example less than 70, such as 65, for    example less than 60, such as less than 55, for example less than    50, such as 45, for example less than 40, such as less than 35, for    example less than 30, such as 25, for example less than 20, such as    less than 15, for example less than 10, such as 5, for example less    than 1 IU/cm².-   73. The matrix material according to item 71, wherein the surface of    the matrix contains between 1-5 IU/cm² thrombin, such as 5-10, for    example 10-15, such as 15-20, for example 20-25, such as 25-30, for    example 30-35, such as 35-40, for example 40-45, such as 45-50, for    example 50-55, such as 55-60, for example 60-65, such as 65-70, for    example 70-75, such as 75-80, for example 80-85, such as 85-90, for    example 90-95, such as 95-100, for example 100-110, such as 110-120,    for example 120-130, such as 130-140, for example 140-150, such as    150-160, for example 160-170, such as 170-180, for example 180-190,    such as 190-200, for example 200-210, such as 210-220, for example    220-230, such as 230-240, for example 240-250, such as 250-260, for    example 260-270, such as 270-280, for example 280-290, such as    290-300 IU/cm².-   74. The matrix material according to item 1, wherein the    pharmaceutical composition is printed onto the surface of the matrix    material by deposition of an amount of liquid per position of less    than 100 nL, such as less than 90 nL, for example less than 80 nL,    such as less than 70 nL, for example less than 60 nL, such as less    than 50 nL, for example less than 40 nL, such as less than 30 nL,    for example less than 20 nL, such as less than 10 nL, for example    less than 1 nL or 1000 pL, such as less than 900 pL, for example    less than 800 pL, such as less than 700 pL, for example less than    600 pL, such as less than 500 pL, for example less than 400 pL, such    as less than 300 pL, for example less than 250 pL, such as less than    200 pL, for example less than 150 pL, such as less than 100 pL, for    example less than 90 pL, such as less than 80 pL, for example less    than 70 pL, such as less than 60 pL, for example less than 50 pL,    such as less than 40 pL, for example less than 30 pL, such as less    than 20 pL, for example less than 10 pL, such as less than 9 pL, for    example less than 8 pL, such as less than 7 pL, for example less    than 6 pL, such as less than 5 pL, for example less than 4 pL, such    as less than 3 pL, for example less than 2 pL, such as less than 1    pL per position.-   75. The matrix material according to item 1, wherein the    pharmaceutical composition is printed onto the surface of the matrix    material by deposition of an amount of liquid per position in pico    litre (pL) to nano litre (nL) range, such as 1-10 pL, for example    10-20 pL, such as 20-30 pL, for example 30-40 pL, such as 40-50 pL,    for example 50-60 pL, such as 60-70 pL, for example 70-80 pL, such    as 80-90 pL, for example 100-150 pL, such as 150-200 pL, for example    200-250 pL, such as 250-300 pL, for example 300-400 pL, such as    400-500 pL, for example 500-600 pL, such as 600-700 pL, for example    700-800 pL, such as 800-900 pL, for example 900-1000 pL or 1 nL,    such as 1-10 nL, for example 10-20 nL, such as 20-30 nL, for example    30-40 nL, such as 40-50 nL, for example 50-60 nL, such as 60-70 nL,    for example 70-80 nL, such as 80-90 nL, for example 90-100 nL.-   76. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more adhesive agents.-   77. The matrix material according to item 76, wherein the one or    more adhesive agents can be selected from the group consisting of    saccharides, monosaccharides, disaccharides, oligosaccharides,    polysaccharides, glucose, mannose, fructose, threose, gulose,    arabinose, ribose, erythrose, lyxose, galactose, sorbose, altrose,    tallose, idose, rhamnose, allose, pentosamines, hexosamines,    glucosamine, N-acetylglucosamine, glucoronic acid, sucrose, maltose,    lactose, cellubiose, glycogen, chitin, chitosan, starch, potato    starch, glycosaminoglycans, chondroitin, chondroitin sulfate,    hyaluronic acid, dermatan sulphate, keratan sulphate, aminated    dextrans, DEAE-dextran, aminated starch, aminated glycogen, aminated    cellulose, aminated pectin, and salts, complexes, derivatives and    mixtures thereof.-   78. The matrix material according to item 76, wherein the one or    more adhesive agents can be selected from the group consisting of    hydrocarbon resins, rosin resins, terpene resins, Escorez® from    ExxonMobil; Regalite®, Piccotac® and Picco® from Eastman; Indopol®    from BP or Arkon®, esters of hydrogenated wood rosin,    pentaerythritol ester of hydrogenated wood rosin, esters of    partially hydrogenated wood rosin, pentaerythritol esters of    partially hydrogenated wood rosin, esters of wood rosin, esters of    modified wood rosin, esters of partially dimerized rosin, esters of    tall oil rosin, esters of dimerized rosin, Foral®, Foralyn®,    Pentalyn®, Permalyn® and Staybelite®.-   79. The matrix material according to item 76, wherein the one or    more adhesive agents can be selected from the group consisting of    Gum Karaya, Sterculia gum, Gum Arabicum, Gum Karrageenan,    celluloseethers, sodium carboxymethylcellulose, Manuba Honey,    casein, alginates and fatty acid esters.-   80. The matrix material according to item 76, wherein the one or    more adhesive agents comprises between 0.1-50% (w/w) of the    pharmaceutical composition, based on the total weight of the    composition such as 1-25% (w/w), such as 5-20% (w/w), e.g. 5-15%    (w/w), 5-10% (w/w), or 10-15% (w/w), based on the total weight of    the composition.-   81. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more surfactant agents.-   82. The matrix material according to item 81, wherein the one or    more surfactant agents can be selected from the group consisting of    anionic surfactants, cationic surfactants, non-ionic surfactants and    surface active biological modifiers.-   83. The matrix material according to item 81, wherein the one or    more surfactant agents can be selected from the group consisting of    potassium laurate, triethanolamine stearate, sodium lauryl sulfate,    sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium    alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol,    phosphatidyl inositol, phosphatidylserine, phosphatidic acid and    their salts, glyceryl esters, sodium carboxymethylcellulose, bile    acids and their salts, cholic acid, deoxycholic acid, glycocholic    acid, taurocholic acid, glycodeoxycholic acid, and calcium    carboxymethylcellulose.-   84. The matrix material according to item 81, wherein the one or    more surfactant agents can be selected from the group consisting of    samples of cationic surfactants include surfactants selected from    the group consisting of quaternary ammonium compounds, benzalkonium    chloride, cetyltrimethylammonium bromide, chitosans and    lauryldimethylbenzylammonium chloride.-   85. The matrix material according to item 81, wherein the one or    more surfactant agents can be selected from the group consisting of    polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty    acid esters, polyoxyethylene fatty acid esters, sorbitan esters,    polyoxyethylene sorbitan esters (such as Tween 80 or Tween 20),    glycerol monostearate, polyethylene glycols, polypropylene glycols,    cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl    polyether alcohols, polyoxyethylene-polyoxypropylene copolymers,    polaxamines, methylcellulose, hydroxycellulose, hydroxy    propylcellulose, hydroxy propylmethylcellulose, noncrystalline    cellulose, polysaccharides, starch, starch derivatives,    hydroxyethylstarch, polyvinyl alcohol, Pluronic F68, and    polyvinylpyrrolidone.-   86. The matrix material according to item 1, wherein the    pharmaceutical composition comprises a solvent component and/or a    fluid component.-   87. The matrix material according to item 86, wherein the solvent    component and/or fluid component is an aqueous medium.-   88. The matrix material according to item 87, wherein the aqueous    medium contains one or more salts such as sodium chloride.-   89. The matrix material according to item 87, wherein the solvent    component and/or fluid component is a volatile fluid.-   90. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more water content    stabilizer such as sorbitol, polysaccaharides or polyols.-   91. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more long chain    molecules (polymers) such as gelatin, starch, polyethlyleneoxide,    polyvinylalcohol and polyethyleneglycols (macrogol).-   92. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one or more substances that    increases the viscosity of the composition, selected from acacia,    alginic acid, bentonite, carbomer, carboxymethylcellulose calcium,    carboxymethylcellulose sodium, cetostearyl alcohol, colloidal    silicon dioxide, guar gum, hydroxyethyl cellulose, hydroxypropyl    cellulose, hydroxypropyl methylcellulose, hydroxypropyl    methylcellulose phtalate, magnesium aluminium silicate,    methylcellulose, microcrystalline cellulose, polyvinyl alcohol,    povidone, sodium alginate, sucrose, tragacanth, gelatin, starch,    albumin, casein, polyethlyleneoxide, polyvinylalcohol,    polyethyleneglycols (macrogol), glycerine (1,2,3-propanetriol) and    glycol (1,2-propanediol).-   93. The matrix material according to item 1, wherein the    pharmaceutical composition has a viscosity in the range of 0.1-20    cps; for example 0.1-1 cps, such as 1-2 cps, for example 2-3 cps,    such as 3-4 cps, for example 4-5 cps, such as 5-6 cps, for example    6-7 cps, such as 7-8 cps, for example 8-9 cps, such as 9-10 cps, for    example 10-11 cps, such as 11-12 cps, for example 12-13 cps, such as    13-14 cps, for example 14-15 cps, such as 15-16 cps, for example    16-17 cps, such as 17-18 cps, for example 18-19 cps, such as 19-20    cps.-   94. The matrix material according to item 1, wherein the    pharmaceutical composition has a surface tension in the range of    0.020 to 0.050 N/m; for example 0.020-0.022 N/m, such as 0.022-0.024    N/m, for example 0.024-0.026 N/m, such as 0.026-0.028 N/m, for    example 0.028-0.030 N/m, such as 0.030-0.032 N/m, for example    0.032-0.034 N/m, such as 0.034-0.036 N/m, for example 0.036-0.038    N/m, such as 0.038-0.040 N/m, for example 0.040-0.042 N/m, such as    0.042-0.044 N/m, for example 0.044-0.046 N/m, such as 0.046-0.048    N/m, for example 0.048-0.050 N/m.-   95. The matrix material according to item 1, wherein the    pharmaceutical composition has a temperature in the range from    sub-zero degrees celcius to 150 degrees celcius; such as −100° C. to    −50° C., for example −50° C. to 0° C., such as 0-10° C., for example    10-20° C., such as 20-30° C., for example 30-40° C., such as 40-50°    C., for example 50-60° C., such as 60-70° C., for example 70-80° C.,    such as 80-90° C., for example 90-100° C., such as 100-125° C., for    example 125-150° C.-   96. The matrix material according to item 1, wherein the    pharmaceutical composition comprises one bioactive agent.-   97. The matrix material according to item 1, wherein the    pharmaceutical composition comprises two or more agents or bioactive    agents.-   98. The matrix material according to item 1, wherein the surface of    the matrix material comprises one pharmaceutical composition    comprising one or more bioactive agents.-   99. The matrix material according to item 1, wherein the surface of    the matrix material comprises two or more different pharmaceutical    compositions each comprising one or more agents or bioactive agents.-   100. The matrix material according to item 99, wherein the two or    more different pharmaceutical compositions are each printed onto the    surface of the matrix material in discrete and non-overlapping    positions of said surface.-   101. The matrix material according to item 100, wherein the two or    more different pharmaceutical compositions are incompatible if    contained in the same pharmaceutical composition.-   102. The matrix material according to item 101, wherein the two or    more different pharmaceutical compositions are separate components    of a two-component glue.-   103. The matrix material according to item 102, wherein said    two-component glue is a surgical glue.-   104. The matrix material according to item 100, wherein the two or    more pharmaceutical compositions comprise thrombin and fibrinogen,    respectively-   105. The matrix according to item 1, wherein said pharmaceutical    composition is uniformly distributed.-   106. The matrix according to item 105, wherein a predetermined ratio    of droplet volume of the pharmaceutical composition, distance    between any two droplets deposited on the surface of said matrix    material and the concentration of a bioactive agent in said    pharmaceutical composition is used.-   107. The matrix material according to item 105, wherein any two area    units of said matrix material differ in volume of the pharmaceutical    composition or concentration of bioactive agent of the    pharmaceutical composition by the most 10%, such as by the most 8%,    for example by the most 6%, such as by the most 4%, for example by    the most 2%, such as by the most 1%.-   108. A matrix according to any of items 1 to 107, said matrix being    obtained by a method comprising the steps of providing a matrix    material and printing said at least one pharmaceutical composition    onto the surface of said matrix material at individual and discrete    locations.-   109. The matrix according to item 108, wherein said method does not    employ a drying step.-   110. The matrix according to item 108, wherein said method    essentially does not alter the physical characteristics and    appearence of the matrix.-   111. The matrix according to item 108, wherein said method    essentially does not alter the physical characteristics of the    surface of said matrix.-   112. The matrix according to item 108, wherein said method    essentially does not cause any swelling of the matrix.-   113. The matrix according to item 108, wherein said method    essentially does not cause any swelling of the surface of said    matrix.-   114. The matrix according to item 108, wherein said method    essentially does not alter the initial absorption rate of the    matrix.-   115. The matrix according to item 108, wherein said method    essentially does not lower the initial absorption rate of the    surface of said matrix.-   116. The matrix according to item 108, wherein said method    essentially does not generate aerosols.-   117. The matrix according to item 108, wherein the amount of fluid    or liquid composition not contacting the matrix material is less    that 10%, such as less than 8%, for example less than 6%, such as    less than 4%, for example less than 2%, such as less than 1%.-   118. The matrix according to item 108, wherein printing of the    pharmaceutical composition occurs essentially perpendicular to the    surface of said matrix material.-   119. The matrix according to item 108, wherein said printing of said    pharmaceutical composition onto the surface of said matrix material    results in the generation of droplets that evaporate within maximum    30 seconds, such as less than 25 seconds, for example less than 20    seconds, such as less than 15 seconds, for example less than 10    seconds, such as less than 5 seconds, for example less than 1 second    after being printed onto the surface of the matrix.-   120. The matrix according to item 108, wherein said printing of said    pharmaceutical composition onto the surface of said matrix material    results in the generation of droplets each with a volume of less    than 100 nL, such as less than 90 nL, for example less than 80 nL,    such as less than 70 nL, for example less than 60 nL, such as less    than 50 nL, for example less than 40 nL, such as less than 30 nL,    for example less than 20 nL, such as less than 10 nL, for example    less than 1 nL or 1000 pL, such as less than 900 pL, for example    less than 800 pL, such as less than 700 pL, for example less than    600 pL, such as less than 500 pL, for example less than 400 pL, such    as less than 300 pL, for example less than 250 pL, such as less than    200 pL, for example less than 150 pL, such as less than 100 pL, for    example less than 90 pL, such as less than 80 pL, for example less    than 70 pL, such as less than 60 pL, for example less than 50 pL,    such as less than 40 pL, for example less than 30 pL, such as less    than 20 pL, for example less than 10 pL, such as less than 9 pL, for    example less than 8 pL, such as less than 7 pL, for example less    than 6 pL, such as less than 5 pL, for example less than 4 pL, such    as less than 3 pL, for example less than 2 pL, such as less than 1    pL per droplet.-   121. The matrix according to item 120, wherein the droplet size of    any two droplets vary less that 10%, such as less than 8%, for    example less than 6%, such as less than 4%, for example less than    2%, such as less than 1%.-   122. The matrix according to item 121, wherein the droplet size of    any two droplets is essentially identical.-   123. The matrix according to item 99, wherein the distance between    every two droplets deposited by printing onto the matrix surface is    less than 2 mm, such as less than 1.9 mm, for example less than 1.8    mm, such as less than 1.7 mm, for example less than 1.6 mm, such as    less than 1.5 mm, for example less than 1.4 mm, such as less than    1.3 mm, for example less than 1.3 mm, such as less than 1.2 mm, for    example less than 1.1 mm, such as less than 1.0 mm, for example less    than 0.9 mm, such as less than 0.8 mm, for example less than 0.7 mm,    such as less than 0.6 mm, for example less than 0.5 mm, such as less    than 0.4 mm, for example less than 0.3 mm, such as less than 0.2 mm,    for example less than 0.1 mm, such as less than 0.09 mm, for example    less than 0.08 mm, such as less than 0.07 mm, for example less than    0.06 mm, such as less than 0.05 mm, for example less than 0.04 mm,    such as less than 0.03 mm, for example less than 0.02 mm, such as    less than 0.01 mm.-   124. The matrix according to item 123, wherein the distance between    every two droplets deposited by printing onto the matrix surface    vary less that 10%, such as less than 8%, for example less than 6%,    such as less than 4%, for example less than 2%, such as less than    1%.-   125. The matrix according to item 124, wherein the distance between    every two droplets deposited by printing onto the matrix surface is    essentially identical.-   126. The matrix according to item 108, wherein said printing of said    pharmaceutical composition onto the surface of said matrix material    results in the generation of droplets, wherein the distance    traversed by any droplet from the print head to the surface of the    matrix material is less than 0.01 mm, such as less than 0.02 mm, for    example less than 0.03 mm, such as less than 0.04 mm, for example    less than 0.05 mm, such as less than 0.06 mm, for example less than    0.07 mm, such as less than 0.08 mm, for example less than 0.09 mm,    such as less than 0.1 mm, for example less than 0.2 mm, such as less    than 0.3 mm, for example less than 0.4 mm, such as less than 0.5 mm,    for example less than 0.6 mm, such as less than 0.7 mm, for example    less than 0.8 mm, such as less than 0.9 mm, for example less than    1.0 mm, such as less than 1.1 mm, for example less than 1.2 mm, such    as less than 1.3 mm, for example less than 1.4 mm, such as less than    1.5 mm, for example less than 1.6 mm, such as less than 1.7 mm, for    example less than 1.8 mm, such as less than 1.9 mm, for example less    than 2.0 mm, such as less than 2.1 mm, for example less than 2.2 mm,    such as less than 2.3 mm, for example less than 2.4 mm, such as less    than 2.5 mm, for example less than 2.6 mm, such as less than 2.7 mm,    for example less than 2.8 mm, such as less than 2.8 mm, for example    less than 3.0 mm, such as less than 3.5 mm, for example less than    4.0 mm, such as less than 4.5 mm, for example less than 5.0 mm, such    as less than 6.0 mm, for example less than 7.0 mm, such as less than    8.0 mm, for example less than 9.0 mm, such as less than 10.0 mm.-   127. The matrix according to item 126, wherein each droplet    traverses a distance from print head to the surface of a matrix    material that varies between each droplet within a range of 0.01% to    a maximum of 10%; such as 0.01 to 0.1%, for example 0.1 to 1%, such    as 1 to 2%, for example 2 to 3%, such as 3 to 4%, for example 4 to    5%, such as 5 to 6%, for example 6 to 7%, such as 7 to 8%, for    example 8 to 9%, such as 9 to 10%.-   128. The matrix according to item 127, wherein the distance each    droplet traverses from print head to the surface of a matrix    material is essentially identical.-   129. The matrix according to item 108, wherein a print head ejects    droplets at a velocity in the range of 0.1-100 m/sec; such as 0.1-1    m/sec, for example 1-2 m/sec, such as 2-3 m/sec, for example 3-4    m/sec, such as 4-5 m/sec, for example 5-6 m/sec, such as 6-7 m/sec,    for example 7-8 m/sec, such as 8-9 m/sec, for example 9-10 m/sec,    such as 10-15 m/sec, for example 15-20 m/sec, such as 20-30 m/sec,    for example 30-40 m/sec, such as 40-50 m/sec, for example 50-60    m/sec, such as 60-70 m/sec, for example 70-80 m/sec, such as 80-90    m/sec, for example 90-100 m/sec.-   130. The matrix according to item 129, wherein the velocity between    each droplet varies within a range of 0.01% to a maximum of 10%;    such as 0.01 to 0.1%, for example 0.1 to 1%, such as 1 to 2%, for    example 2 to 3%, such as 3 to 4%, for example 4 to 5%, such as 5 to    6%, for example 6 to 7%, such as 7 to 8%, for example 8 to 9%, such    as 9 to 10%.-   131. The matrix according to item 130, wherein the velocity of each    droplet from print head to the surface of a matrix material is    essentially identical.-   132. The matrix material according to item 108, wherein said    pharmaceutical composition is printed onto said surface of said    matrix by jet or inkjet printing.-   133. The matrix material according to item 132, wherein the inkjet    printing comprises piezoelectric jet printing.-   134. The matrix material according to item 132, wherein the jet    printing comprises thermal jet printing.-   135. The matrix material according to item 132, wherein the inkjet    printing comprises continuous inkjet printing.-   136. The matrix material according to item 132, wherein said inkjet    printing comprises at least one print head comprising at least one    nozzle.-   137. The matrix material according to item 136, wherein the nozzle    diameter is in the range of 1-1000 microns; such as 1-5 microns, for    example 5-10 microns, such as 10-20 microns, for example 20-30    microns, such as 30-40 microns, for example 40-50 microns, such as    50-60 microns, for example 60-70 microns, such as 70-80 microns, for    example 80-90 microns, such as 90-100 microns, for example 100-200    microns, such as 200-300 microns, for example 300-400 microns, such    as 400-500 microns, for example 500-600 microns, such as 600-700    microns, for example 700-800 microns, such as 800-900 microns, for    example 900-1000 microns.-   138. The matrix material according to item 136, wherein the at least    one print head comprises between 1-50, 50-100, 100-150, 150-200,    200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-600,    600-700, 700-800, 800-900, 900-1000, 1000-1100, 1100-1200,    1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800,    1800-1900, 1900-2000, 2000-2500, 2500-3000, 3000-4000, 4000-5000,    5000-10,000 nozzles per print head.-   139. A device comprising the matrix material printed with a    pharmaceutical composition according to items 1-138.-   140. A kit of parts comprising the device according to item 139 and    at least one additional component.-   141. A method for making the device according to item 139 comprising    the steps of    -   a. providing a matrix material, and    -   b. printing a pharmaceutical composition onto the surface of        said matrix material at individual and discrete locations.-   142. Use of the device according to item 139 to promote wound    healing in an individual in need thereof-   143. Use of the device according to item 139 to promote hemostasis    in an individual in need thereof-   144. A matrix material comprising a surface and a plurality of open    and interconnected cells, wherein one or more pharmaceutical    compositions have been applied onto said matrix material.-   145. The matrix material according to item 144, wherein the matrix    comprises one or more polymers.-   146. The matrix material according to item 144, wherein said    polymers are cross-linked.-   147. The matrix material according to item 144, wherein said    polymers are not cross-linked.-   148. The matrix material according to item 145, wherein said    polymers are selected from the group consisting of collagen,    gelatin, polyurethane, polysiloxanes (silicone), hydrogels,    polyacrylamides, chitosan, sodium polyacrylate, agarose, alginates,    xanthan gum, guar gum, arabic gum, agar gum, Locust Bean gum,    Carrageenan gum, Xanthan gum, Karaya gum, tragacanth gum, Ghatti    gum, Furcelleran gum, chitin, cellulose, methylcellulose,    carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl    methylcellulose, hydroxypropyl cellulose, hyaluronic acid, pectin,    starch, glycogen, pentosans, polyoxyethylene, polyAMPS    (poly(2-acrylamido-2-methyl-1-propanesulfonic acid),    polyvinylpyrrolidone, polyvinyl alcohol, polyglycolic acid,    polyacetic acid, acrylate polymers, polyhydroxyalkyl acrylates,    methacrylates, polyvinyl lactams, polyvinyl alcohols,    polyoxyalkylenes, polyacrylamides, polyacrylic acid, polystyrene    sulfonates, synthetic hydrocolloids such as N-vinyl-2-pyrrolidone,    5-methyl-N-vinyl-2-pyrrolidone, 5-ethyl-N-vinyl-2-pyrrolidone,    3,3-dimethyl-N-vinyl-2-pyrrolidone, 3-methyl-N-vinyl-2-pyrrolidone,    3-ethyl-N-vinyl-2-pyrrolidone, 4-methyl-N-vinyl-2-pyrrolidone,    4-ethyl-N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam,    N-vinyl-2-caprolactam, hydroxyalkyl acrylates and methacrylates,    (such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate,    2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate,    2,3-dihydroxypropyl methacrylate), acrylic acid, methacrylic acid,    tertiary amino-methacrylimide, (e.g. trimethylamino-methacrylimide),    crotonic acid, pyridine, water soluble amides, (such as    N-(hydroxymethyl)acrylamide and -methacrylamide,    N-(3-hydroxpropyl)acrylamide, N-(2-hydroxyethyl)methacrylamide,    N-(1,1-dimethyl-3-oxabutyl)acrylamide    N-[2-(dimethylamine)ethyl]acrylamide and -methacrylamide,    N-[3-(dimethylamino)-2-hydroxylpropyl]methacrylamide, and    N-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide);    water-soluble hydrazine derivatives, (such as trialkylamine    methacrylimide, and dimethyl-(2-hydroxypropyl)amine methacrylimide);    mono-olefinic sulfonic acids and their salts, (such as sodium    ethylene sulfonate, sodium styrene sulfonate,    2-acrylamideo-2-methylpropanesulfonic acid), 1-vinyl-imidazole,    1-vinyl-indole, 2-vinyl imidazole, 4(5)-vinyl-imidazole,    2-vinyl-1-methyl-imidazole, 5-vinyl-pyrazoline,    3-methyl-5-isopropenyl-pyrazole, 5-methylene-hydantoin,    3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone,    3-methacrylyl-5-methyl-2-oxazolidone,    3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinyl-pyridine,    5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1-oxide,    3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and    4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine,    4-acrylyl-morpholine, Oxidized Regenerated Cellulose (ORC),    poly(lactic-co-glycolic acid) (PLGA), Polylactic acid (PLA),    Extracellular matrix (ECM) and mixtures thereof-   149. The matrix material according to item 145, wherein the polymers    originates from an animal source such as porcine, bovine or fish    sources.-   150. The matrix material according to item 145, wherein the polymers    are synthetically made i.e. by recombinant means.-   151. The matrix material according to item 145, wherein the polymers    are selected from collagen and gelatin.-   152. The matrix material according to item 145, wherein the polymers    comprise gelatin.-   153. The matrix material according to item 145, wherein the polymers    comprise collagen.-   154. The matrix material according to item 144, wherein the    interconnected open cells form pores having a diameter of from about    0.1 mm to about 5.0 mm.-   155. The matrix material according to item 144, wherein the matrix    has the dimensions (length, width and height) of less than 15 cm    long, less than 10 cm wide and less than 2 cm high.-   156. The matrix material according to item 144, wherein the matrix    is a shape selected from the group consisting of square form,    circular form, rectangular form, cubic form, cylinder form,    spherical or pyramid-shaped.-   157. The matrix material according to item 144, wherein the matrix    has a colour selected from the group consisting of red, pink,    yellow, blue, green, white, black, brown, purple, orange, grey and    turquoise.-   158. The matrix material according to item 144, wherein the matrix    material has a reconformation rate of no more than 10 seconds, such    as no more than 9 seconds, for example no more than 8 seconds, such    as no more than 7 seconds, for example no more than 6 seconds, such    as no more than 5 seconds, for example no more than 4 seconds, such    as no more than 3 seconds, for example no more than 3 seconds, such    as no more than 1 second.-   159. The matrix material according to item 144, wherein the matrix    material has a pore size with a normal distribution around 0.1-1.0    mm.-   160. The matrix material according to item 144, wherein the matrix    material has a pore size of less than 10 mm, such as less than 9 mm,    for example less than 8 mm, such as less than 7 mm, for example less    than 6 mm, such as less than 5 mm, for example less than 4 mm, such    as less than 3 mm, for example less than 2.9 mm, such as less than    2.8 mm, for example less than 2.7 mm, such as less than 2.6 mm, for    example less than 2.5 mm, such as less than 2.4 mm, for example less    than 2.3 mm, such as less than 2.2 mm, for example less than 2.1 mm,    such as less than 2 mm, for example less than 1.9 mm, such as less    than 1.8 mm, for example less than 1.7 mm, such as less than 1.6 mm,    for example less than 1.5 mm, such as less than 1.4 mm, for example    less than 1.3 mm, such as less than 1.2 mm, for example less than    1.1 mm, such as less than 1.0 mm, for example less than 0.9 mm, such    as less than 0.8 mm, for example less than 0.7 mm, such as less than    0.6 mm, for example less than 0.5 mm, such as less than 0.4 mm, for    example less than 0.3 mm, such as less than 0.2 mm, for example less    than 0.1 mm, such as less than 0.05, for example less than 0.01 mm.-   161. The matrix material according to item 144, wherein the matrix    material has a pore size in the range of 0.01-0.1 mm, such as    0.1-0.2 mm, for example 0.2-0.3 mm, such as 0.3-0.4 mm, for example    0.4-0.5 mm, such as 0.5-0.6 mm, for example 0.6-0.7 mm, such as    0.7-0.8 mm, for example 0.8-0.9 mm, such as 0.9-1 mm, for example    1-1.1 mm, such as 1.1-1.2 mm, for example 1.2-1.3 mm, such as    1.3-1.4 mm, for example 1.4-1.5 mm, such as 1.5-1.6 mm, for example    1.6-1.7 mm, such as 1.7-1.8 mm, for example 1.8-1.9 mm, such as    2-2.1 mm, for example 2.1-2.2 mm, such as 2.2-2.3 mm, for example    2.3-2.4 mm, such as 2.4-2.5 mm, for example 2.5-2.6 mm, such as    2.6-2.7 mm, for example 2.7-2.8 mm, such as 2.8-2.9 mm, for example    2.9-3 mm, such as 3-4 mm, for example 4-5 mm, such as 5-6 mm, for    example 6-7 mm, such as 7-8 mm, for example 8-9 mm, such as 9-10 mm.-   162. The matrix material according to item 144, wherein the matrix    material has a modulus in the range of 0.1-50 GPa, such as 0.1-1,    for example 1-2, such as 2-3, such as 3-4, for example 4-5, such as    5-6, for example, 6-7, such as 7-8, for example 8-9, such as 9-10,    for example 10-20, such as 20-30, for example 30-40, such as 40-50    GPa.-   163. The matrix material according to item 144, wherein the matrix    contains less than 100 IU/cm² (units per square centimeter), such as    less than 95, for example less than 90, such as 85, for example less    than 80, such as less than 75, for example less than 70, such as 65,    for example less than 60, such as less than 55, for example less    than 50, such as 45, for example less than 40, such as less than 35,    for example less than 30, such as 25, for example less than 20, such    as less than 15, for example less than 10, such as 5, for example    less than 1 IU/cm² of the pharmaceutical composition.-   164. The matrix material according to item 144, wherein the surface    of the matrix contains between 1-5 IU/cm², such as 5-10, for example    10-15, such as 15-20, for example 20-25, such as 25-30, for example    30-35, such as 35-40, for example 40-45, such as 45-50, for example    50-55, such as 55-60, for example 60-65, such as 65-70, for example    70-75, such as 75-80, for example 80-85, such as 85-90, for example    90-95, such as 95-100 IU/cm² of the pharmaceutical composition.-   165. The matrix material according to item 144, wherein the matrix    material is a sponge.-   166. The matrix material according to item 144, wherein the sponge    is a gelatin or collagen sponge.-   167. The matrix material according to item 166, wherein the gelatin    or collagen sponge is selected from the group consisting of    Spongostan, Surgifoam, Surgiflo (all Ferrosan A/S), Collastat    (Kendall Co.), Avitene (Avicon Inc.), Surgicel, Surgifoam (both    Johnson & Johnson) and Gelfoam (Phizer).-   168. The matrix material according to item 144, wherein the matrix    material is a patch.-   169. The matrix material according to item 144, wherein the matrix    material is a swab.-   170. The matrix material according to item 144, wherein the matrix    material is a bandage.-   171. The matrix material according to item 144, wherein the matrix    material is a wound dressing,-   172. The matrix material according to item 144, wherein the matrix    material is a tissue dressing.-   173. The matrix material according to item 144, wherein the matrix    material is sterile.-   174. The matrix material according to item 144, wherein the matrix    material is sterile and contained in a sterile, pre-packaged,    ready-to-use container.-   175. The matrix material according to item 144, wherein the matrix    material is sterilized.-   176. The matrix material according to item 144, wherein the matrix    material is sterilized by application of heat.-   177. The matrix material according to item 144, wherein the matrix    material is sterilized by application of one or more chemicals.-   178. The matrix material according to item 144, wherein the matrix    material is sterilized by application of high pressure.-   179. The matrix material according to item 144, wherein the matrix    material is sterilized by application of filtration.-   180. The matrix material according to item 144, wherein the matrix    material is sterilized by application of autoclaving.-   181. The matrix material according to item 144, wherein the matrix    material is sterilized by application of radiation sterilization    such as sterilization using X-rays, gamma rays, UV light and/or    subatomic particles.-   182. The matrix material according to item 144, wherein the matrix    material is sterilized by application of chemical sterilization    include use of one or more of the chemicals selected from the group    consisting of ethylene oxide gas, ozone, chlorine bleach,    glutaraldehyde, formaldehyde, ortho phthalaldehyde, hydrogen    peroxide and peracetic acid.-   183. The matrix material according to item 175, wherein the sterile    matrix material is contained in a sterile container and separated    from an external, non-sterile environment.-   184. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates hemostasis.-   185. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates wound healing.-   186. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates wound healing by inhibition of one or more    infections of the wound.-   187. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises one or more anti-fibrinolytic agents.-   188. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises one or more pro-coagulants.-   189. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates platelets.-   190. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulate formation of a hemostatic plug.-   191. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates one or more coagulation factors.-   192. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    selected from the group consisting of endothelium Tissue Factor    (TF), Factor VII, TF-Factor VIIa, Factor IX, Factor X, thrombin,    Factor XIa, plasmin, Factor XII, Factor Xa, TFPI, Factor Va,    prothrombinase complex, prothrombin, Factor V, Factor XI, Factor    VIII, vWF, Factor VIIIa, Factor IXa and the tenase complex.-   193. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the formation of fibrin strands.-   194. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates platelate aggregation.-   195. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises thrombin.-   196. The matrix material according to items 144 and 195, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises fibrinogen.-   197. The matrix material according to items 144 and 195, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor XIII and/or XIIIa.-   198. The matrix material according to items 144 and 195, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises tranexamic acid.-   199. The matrix material according to items 144 and 195, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Willebrand factor (vWF).-   200. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the contact activation pathway.-   201. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates the tissue factor pathway.-   202. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates fibrin formation.-   203. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    that stimulates fibrin cross-linking.-   204. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor VIII.-   205. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor V.-   206. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor XIII.-   207. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which comprises Factor VII.-   208. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more bioactive agent(s)    which stimulates the coagulation cascade.-   209. The matrix material according to item 144, wherein the    pharmaceutical composition comprises thrombin.-   210. The matrix material according to item 209, wherein the matrix    contains less than 300 IU thrombin per square cm (cm²) surface area,    such as less than 290, for example less than 280, such as 270, for    example less than 260, such as less than 250, for example less than    240, such as 230, for example less than 220, such as less than 210,    for example less than 200, such as 190, for example less than 180,    such as less than 170, for example less than 160, such as 150, for    example less than 140, such as less than 130, for example less than    120, such as 110, for example less than 100 IU/cm², such as less    than 95, for example less than 90, such as 85, for example less than    80, such as less than 75, for example less than 70, such as 65, for    example less than 60, such as less than 55, for example less than    50, such as 45, for example less than 40, such as less than 35, for    example less than 30, such as 25, for example less than 20, such as    less than 15, for example less than 10, such as 5, for example less    than 1 IU/cm².-   211. The matrix material according to item 209, wherein the surface    of the matrix contains between 1-5 IU/cm², such as 5-10, for example    10-15, such as 15-20, for example 20-25, such as 25-30, for example    30-35, such as 35-40, for example 40-45, such as 45-50, for example    50-55, such as 55-60, for example 60-65, such as 65-70, for example    70-75, such as 75-80, for example 80-85, such as 85-90, for example    90-95, such as 95-100, for example 100-110, such as 110-120, for    example 120-130, such as 130-140, for example 140-150, such as    150-160, for example 160-170, such as 170-180, for example 180-190,    such as 190-200, for example 200-210, such as 210-220, for example    220-230, such as 230-240, for example 240-250, such as 250-260, for    example 260-270, such as 270-280, for example 280-290, such as    290-300 IU/cm².-   212. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more adhesive agents.-   213. The matrix material according to item 212, wherein the one or    more adhesive agents can be selected from the group consisting of    saccharides, monosaccharides, disaccharides, oligosaccharides,    polysaccharides, glucose, mannose, fructose, threose, gulose,    arabinose, ribose, erythrose, lyxose, galactose, sorbose, altrose,    tallose, idose, rhamnose, allose, pentosamines, hexosamines,    glucosamine, N-acetylglucosamine, glucoronic acid, sucrose, maltose,    lactose, cellubiose, glycogen, chitin, chitosan, starch, potato    starch, glycosaminoglycans, chondroitin, chondroitin sulfate,    hyaluronic acid, dermatan sulphate, keratan sulphate, aminated    dextrans, DEAE-dextran, aminated starch, aminated glycogen, aminated    cellulose, aminated pectin, and salts, complexes, derivatives and    mixtures thereof.-   214. The matrix material according to item 212, wherein the one or    more adhesive agents can be selected from the group consisting of    hydrocarbon resins, rosin resins, terpene resins, Escorez® from    ExxonMobil; Regalite®, Piccotac® and Picco® from Eastman; Indopol®    from BP or Arkon®, esters of hydrogenated wood rosin,    pentaerythritol ester of hydrogenated wood rosin, esters of    partially hydrogenated wood rosin, pentaerythritol esters of    partially hydrogenated wood rosin, esters of wood rosin, esters of    modified wood rosin, esters of partially dimerized rosin, esters of    tall oil rosin, esters of dimerized rosin, Foral®, Foralyn®,    Pentalyn®, Permalyn® and Staybelite®.-   215. The matrix material according to item 212, wherein the one or    more adhesive agents can be selected from the group consisting of    Gum Karaya, Sterculia gum, Gum Arabicum, Gum Karrageenan,    celluloseethers, sodium carboxymethylcellulose, Manuba Honey,    casein, alginates and fatty acid esters.-   216. The matrix material according to item 212, wherein the one or    more adhesive agents comprises between 0.1-50% (w/w) of the    pharmaceutical composition, based on the total weight of the    composition such as 1-25% (w/w), such as 5-20% (w/w), e.g. 5-15%    (w/w), 5-10% (w/w), or 10-15% (w/w), based on the total weight of    the composition.-   217. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more surfactant agents.-   218. The matrix material according to item 217, wherein the one or    more surfactant agents can be selected from the group consisting of    anionic surfactants, cationic surfactants, non-ionic surfactants and    surface active biological modifiers.-   219. The matrix material according to item 217, wherein the one or    more surfactant agents can be selected from the group consisting of    potassium laurate, triethanolamine stearate, sodium lauryl sulfate,    sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium    alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol,    phosphatidyl inositol, phosphatidylserine, phosphatidic acid and    their salts, glyceryl esters, sodium carboxymethylcellulose, bile    acids and their salts, cholic acid, deoxycholic acid, glycocholic    acid, taurocholic acid, glycodeoxycholic acid, and calcium    carboxymethylcellulose.-   220. The matrix material according to item 217, wherein the one or    more surfactant agents is a cationic surfactant selected from the    group consisting of quaternary ammonium compounds, benzalkonium    chloride, cetyltrimethylammonium bromide, chitosans and    lauryldimethylbenzylammonium chloride.-   221. The matrix material according to item 217, wherein the one or    more surfactant agents can be selected from the group consisting of    polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty    acid esters, polyoxyethylene fatty acid esters, sorbitan esters,    polyoxyethylene sorbitan esters (such as Tween 80 or Tween 20),    glycerol monostearate, polyethylene glycols, polypropylene glycols,    cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl    polyether alcohols, polyoxyethylene-polyoxypropylene copolymers,    polaxamines, methylcellulose, hydroxycellulose, hydroxy    propylcellulose, hydroxy propylmethylcellulose, noncrystalline    cellulose, polysaccharides, starch, starch derivatives,    hydroxyethylstarch, polyvinyl alcohol, Pluronic F68 and    polyvinylpyrrolidone.-   222. The matrix material according to item 144, wherein the    pharmaceutical composition comprises a solvent component and/or a    fluid component.-   223. The matrix material according to item 222, wherein the solvent    component and/or fluid component is an aqueous medium.-   224. The matrix material according to item 223, wherein the aqueous    medium contains one or more salts such as sodium chloride.-   225. The matrix material according to item 222, wherein the solvent    component and/or fluid component is a volatile fluid.-   226. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more water content    stabilizer such as sorbitol, polysaccaharides or polyols.-   227. The matrix material according to item 144, wherein the    pharmaceutical composition comprises one or more substances that    increases the viscosity of the composition, selected from acacia,    alginic acid, bentonite, carbomer, carboxymethylcellulose calcium,    carboxymethylcellulose sodium, cetostearyl alcohol, colloidal    silicon dioxide, guar gum, hydroxyethyl cellulose, hydroxypropyl    cellulose, hydroxypropyl methylcellulose, hydroxypropyl    methylcellulose phtalate, magnesium aluminium silicate,    methylcellulose, microcrystalline cellulose, polyvinyl alcohol,    povidone, sodium alginate, sucrose, tragacanth, gelatin, starch,    albumin, casein, polyethlyleneoxide, polyvinylalcohol,    polyethyleneglycols (macrogol), glycerine (1,2,3-propanetriol) and    glycol (1,2-propanediol).-   228. The matrix material according to item 144, wherein the    pharmaceutical composition has a viscosity in the range of 0.1-20    cps; for example 0.1-1 cps, such as 1-2 cps, for example 2-3 cps,    such as 3-4 cps, for example 4-5 cps, such as 5-6 cps, for example    6-7 cps, such as 7-8 cps, for example 8-9 cps, such as 9-10 cps, for    example 10-11 cps, such as 11-12 cps, for example 12-13 cps, such as    13-14 cps, for example 14-15 cps, such as 15-16 cps, for example    16-17 cps, such as 17-18 cps, for example 18-19 cps, such as 19-20    cps.-   229. The matrix material according to item 144, wherein the    pharmaceutical composition has a surface tension in the range of    0.020 to 0.050 N/m; for example 0.020-0.022 N/m, such as 0.022-0.024    N/m, for example 0.024-0.026 N/m, such as 0.026-0.028 N/m, for    example 0.028-0.030 N/m, such as 0.030-0.032 N/m, for example    0.032-0.034 N/m, such as 0.034-0.036 N/m, for example 0.036-0.038    N/m, such as 0.038-0.040 N/m, for example 0.040-0.042 N/m, such as    0.042-0.044 N/m, for example 0.044-0.046 N/m, such as 0.046-0.048    N/m, for example 0.048-0.050 N/m.-   230. The matrix material according to item 144, wherein the    pharmaceutical composition has a temperature is in the range from    sub-zero degrees celcius to 150 degrees celcius; such as −100° C. to    −50° C., for example −50° C. to 0° C., such as 0-10° C., for example    10-20° C., such as 20-30° C., for example 30-40° C., such as 40-50°    C., for example 50-60° C., such as 60-70° C., for example 70-80° C.,    such as 80-90° C., for example 90-100° C., such as 100-125° C., for    example 125-150° C.-   231. The matrix material according to item 144, wherein the one or    more pharmaceutical compositions are deposited into and/or onto said    matrix material by spraying of the one or more pharmaceutical    compositions into and/or onto said matrix.-   232. The matrix material according to item 144, wherein the one or    more pharmaceutical compositions are deposited into and/or onto said    matrix material by sprinkling of the one or more pharmaceutical    compositions into and/or onto said matrix.-   233. The matrix material according to item 144, wherein the one or    more pharmaceutical compositions are deposited into and/or onto said    matrix material by pouring of the one or more pharmaceutical    compositions into and/or onto said matrix.-   234. The matrix material according to item 144, wherein the one or    more pharmaceutical compositions are deposited into and/or onto said    matrix material by dipping of said matrix into the one or more    pharmaceutical compositions.-   235. The matrix material according to item 144, wherein the one or    more pharmaceutical compositions are deposited into or onto the    matrix during preparation of said matrix.-   236. A device comprising the matrix material and a pharmaceutical    composition according to items 144-235.-   237. A kit of parts comprising the device according to item 236 and    at least one additional component.-   238. A method for making the device according to item 236 comprising    the steps of    -   a. providing a matrix material, and    -   b. applying a pharmaceutical composition onto the surface of        said matrix material at individual and discrete locations.-   239. Use of the device according to item 236 to promote wound    healing in an individual in need thereof-   240. Use of the device according to item 236 to promote hemostasis    in an individual in need thereof.-   241. A matrix material comprising a surface and a plurality of open    and interconnected cells, wherein said matrix material comprises a    haemostatically effective amount of thrombin or a precursor thereof.-   242. The matrix material according to item 241, wherein said matrix    further comprises one or more thrombin-stabilizing agents.-   243. The matrix material according to item 241, wherein said    thrombin is applied to the matrix material by e.g. printing,    spraying, soaking, dipping, coating, saturating, pressuring,    sprinkling, pouring, spreading, greasing, smearing, dabbing, rubbing    or painting.-   244. The matrix material according to item 241, wherein the matrix    material comprises a biologically absorbable material comprising    thrombin.-   245. The matrix material according to item 241, wherein the matrix    material comprises a sponge comprising thrombin.-   246. The matrix material according to item 241, wherein the matrix    material comprises a gelatin foam pad and/or a gauze pad that    provide a unique, premixed, sterile, gelatin/thrombin haemostat.-   247. The matrix material according to item 241, wherein the matrix    material comprises a premixed thrombin/gelatin pad.-   248. The matrix material according to item 241, wherein the matrix    material comprises thrombin freeze-dried into a gelatin foam.-   249. The matrix material according to item 241, wherein the matrix    material comprises any standard gelatin pad with thrombin.-   250. The matrix material according to item 241, wherein the matrix    material comprises a fibrin paste based on e.g. a collagen sponge    coated with fibrinogen and/or thrombin.-   251. The matrix material according to item 241, wherein the matrix    material comprises Thrombi-Gel® (Vascular Solutions, Inc.).-   252. The matrix material according to item 241, wherein the matrix    material comprises Thrombi-Pad™ (Vascular Solutions, Inc.).-   253. The matrix material according to item 241, wherein the matrix    material comprises D-Stat Dry product (such as D-Stat Dry, D-Stat 2    Dry) (Vascular Solutions, Inc.).-   254. The matrix material according to item 241, wherein the matrix    material comprises ThrombiGel hemostatic foam (Vascular Solutions,    Inc.).-   255. The matrix material according to item 241, wherein the matrix    material comprises Gelfoam (Pfizer).-   256. The matrix material according to item 241, wherein the matrix    material comprises Surgifoam (Johnson & Johnson).-   257. The matrix material according to item 241, wherein the matrix    material comprises Surgiflo (Johnson & Johnson).-   258. The matrix material according to item 241, wherein the matrix    material comprises FloSeal Matrix Hemostatic Sealant (Baxter    International Inc.).-   259. The matrix material according to item 241, wherein the matrix    material comprises TachoSil (Nycomed).-   260. The matrix material according to item 241, wherein the matrix    material comprises a collagen material such as Avitene, Actifoam,    Helistat, Inistat, or CoStasis hemostatic device.-   261. The matrix material according to item 241, wherein the matrix    material comprises a cellulose material such as Surgicel    (Ethicon/Johnson & Johnson), Oxycel or Tabotamp.-   262. The matrix material according to item 241, wherein the thrombin    is Thrombostat, Thrombin-JMI (King Pharmaceuticals), Recothrom    (Bayer/Zymogenetics), Evithrom (OMRIX Biopharmaceuticals/Ethicon),    or any other commercially available thrombin.-   263. The matrix material according to item 241, wherein the thrombin    is produced from plasma using the Thrombin Activation Device (TAD)    (Thermogenesis).-   264. The matrix material according to item 241, wherein the matrix    material comprises a hemostatic paste composition comprising a    hemostatic effective amount of thrombin in a polyethylene glycol    base which is preferably prepared by admixing an aqueous solution of    thrombin and polyethylene glycol and freeze-drying the mixture to    remove substantially all of the water to yield a viscous water    soluble paste of fine particles of thrombin uniformly dispersed    throughout the polyethylene glycol base (as described in U.S. Pat.    No. 5,595,735).-   265. The matrix material according to item 241, wherein the matrix    material comprises a collagen paste hemostat comprising thrombin    e.g. as described in U.S. Pat. No. 4,891,359.-   266. The matrix material according to item 241, wherein the matrix    material comprises a stable collagen sponge having thrombin therein    e.g. as described in U.S. Pat. No. 4,515,637.-   267. The matrix material according to item 241, wherein the matrix    material comprises a collagen sponge having thrombin therein e.g. as    described in U.S. Pat. No. 6,649,162.-   268. A device comprising the matrix material and thrombin according    to items 241-267.-   269. A kit of parts comprising the device according to item 268 and    at least one additional component.-   270. A method for making the device according to item 268 comprising    the steps of    -   a. providing a matrix material, and    -   b. printing thrombin onto the surface of said matrix material at        individual and discrete locations.-   271. Use of the device according to item 268 to promote wound    healing in an individual in need thereof-   272. Use of the device according to item 268 to promote hemostasis    in an individual in need thereof-   273. A container for storage and/or preparation of a matrix material    comprising    -   i) a bottom,    -   ii) one or more sidewall(s) continuously surrounding said        bottom,    -   iii) a sealing surface for a lid, and    -   iv) a lid,    -   wherein the one or more sidewall(s) and the bottom defines an        inner cavity suitable for storage and/or preparation of a matrix        material.-   274. The container according to item 273, wherein the one or more    sidewalls comprises one or more marks for maximum filling of the    container with a liquid.-   275. The container according to item 274, wherein the mark for    maximum filling is a bevelled edge on the one or more sidewalls.-   276. The container according to item 274, wherein the mark for    maximum filling is a line.-   277. The container according to item 274, wherein the mark for    maximum filling is a dot.-   278. The container according to item 274, wherein the mark for    maximum filling is a dent in the one or more sidewalls.-   279. The container according to item 274, wherein said liquid is    selected from the group consisting of an aqueous solution, a saline    solution, medical-grade water or others.-   280. The container according to item 273, wherein the inner cavity    comprises one or more matrix materials.-   281. The container according to item 273, wherein the inner cavity    can circumvent a matrix material.-   282. The container according to item 273, wherein the inner cavity    comprises one or more matrix materials according to items 1 to 103    (matrix material printed with a pharmaceutical composition).-   283. The container according to item 273, wherein the inner cavity    comprises one or more matrix materials according to items 109 to 201    (matrix material with a pharmaceutical composition).-   284. The container according to item 273, wherein the inner cavity    comprises one or more matrix materials according to items 207 to 233    (matrix material with thrombin).-   285. The container according to item 273, wherein the container    comprises one or more handles.-   286. The container according to item 285, wherein the container    comprises one handle.-   287. The container according to item 285, wherein the container    comprises two handles.-   288. The container according to item 285, wherein the one or more    handles are associated with the bottom of the container.-   289. The container according to item 285, wherein the one or more    handles are associated with the one or more sidewall(s) of the    container.-   290. The container according to item 285, wherein the one or more    handles comprises one or more recesses or indentations for improved    grip.-   291. The container according to item 273, wherein the one or more    sidewall(s) comprises one or more recesses or indentations for    improved grip.-   292. The container according to item 273, wherein the container    comprises one or more inner tray notches for easy handling of    product.-   293. The container according to item 292, wherein the container    comprises one inner tray notches.-   294. The container according to item 292, wherein the container    comprises two inner tray notches.-   295. The container according to item 292, wherein the container    comprises three inner tray notches.-   296. The container according to item 292, wherein the container    comprises four inner tray notches.-   297. The container according to item 292, wherein the one or more    inner tray notches are associated with the one or more sidewall(s)    of the container.-   298. The container according to item 273, wherein the lid is    peelable (a peel-off lid).-   299. The container according to item 273, wherein the lid is    reclosable.-   300. The container according to item 273, wherein the inner cavity    is a sterile environment.-   301. The container according to item 273, wherein the container is    sterilized by application of dry heat.-   302. The container according to item 273, wherein the container is    sterilized by application of one or more chemicals.-   303. The container according to item 302, wherein the container is    sterilized by application of chemical sterilization including use of    one or more of the chemicals selected from the group consisting of    ethylene oxide gas, ozone, chlorine bleach, glutaraldehyde,    formaldehyde, ortho phthalaldehyde, hydrogen peroxide and peracetic    acid.-   304. The container according to item 273, wherein the container is    sterilized by application of high pressure.-   305. The container according to item 273, wherein the container is    sterilized by application of radiation sterilization such as    sterilization using X-rays, gamma rays, UV light, microwaves,    electron beam and/or subatomic particles.-   306. The container according to item 273, wherein the bottom of the    inner cavity is formed as a square.-   307. The container according to item 273, wherein the bottom of the    inner cavity is formed as a rectangle.-   308. The container according to item 273, wherein the bottom of the    inner cavity is formed as a triangle.-   309. The container according to item 273, wherein the bottom of the    inner cavity is formed as a circle.-   310. The container according to item 273, wherein the bottom of the    inner cavity is formed as an oval.-   311. The container according to item 273, wherein the bottom of the    inner cavity is formed as a square with dimensions selected from the    group consisting of 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1    cm×5 cm, 1 cm×6 cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1    cm×15 cm, 1 cm×20 cm, 2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2    cm×5 cm, 2 cm×6 cm, 2 cm×7 cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2    cm×15 cm, 2 cm×20 cm, 3 cm×1 cm, 3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3    cm×5 cm, 3 cm×6 cm, 3 cm×7 cm, 3 cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3    cm×15 cm, 3 cm×20 cm, 4 cm×1 cm, 4 cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4    cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4 cm×8 cm, 4 cm×9 cm, 4 cm×10 cm, 4    cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5 cm×2 cm, 5 cm×3 cm, 5 cm×4 cm, 5    cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8 cm, 5 cm×9 cm, 5 cm×10 cm, 5    cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm, 6 cm×3 cm, 6 cm×4 cm, 6    cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9 cm, 6 cm×10 cm, 6    cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm, 7 cm×4 cm, 7    cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7 cm×10 cm, 7    cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8 cm×4 cm, 8    cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8    cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9    cm×5 cm, 9 cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9    cm×15 cm, 9 cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4    cm, 10 cm×5 cm, 10 cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10    cm×10 cm, 10 cm×15 cm, 10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3    cm, 11 cm×4 cm, 11 cm×5 cm, 11 cm×6 cm, 11 cm×7 cm, 11 cm×8 cm, 11    cm×9 cm, 11 cm×10 cm, 11 cm×15 cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2    cm, 12 cm×3 cm, 12 cm×4 cm, 12 cm×5 cm, 12 cm×6 cm, 12 cm×7 cm, 12    cm×8 cm, 12 cm×9 cm, 12 cm×10 cm, 12 cm×15 cm, 12 cm×20 cm, 13 cm×1    cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4 cm, 13 cm×5 cm, 13 cm×6 cm, 13    cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13 cm×10 cm, 13 cm×15 cm, 13 cm×20    cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm, 14 cm×4 cm, 14 cm×5 cm, 14    cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm, 14 cm×10 cm, 14 cm×15    cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3 cm, 15 cm×4 cm, 15    cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm, 15 cm×10    cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3 cm, 16    cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9 cm,    16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17    cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm,    17 cm×9 cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18    cm×2 cm, 18 cm×3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm,    18 cm×8 cm, 18 cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19    cm×1 cm, 19 cm×2 cm, 19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm,    19 cm×7 cm, 19 cm×8 cm, 19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19    cm×20 cm, 20 cm×1 cm, 20 cm×2 cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5    cm, 20 cm×6 cm, 20 cm×7 cm, 20 cm×8 cm, 20 cm×9 cm, 20 cm×10 cm, 20    cm×15 cm, 20 cm×20 cm, 25 cm×1 cm, 25 cm×2 cm, 25 cm×3 cm, 25 cm×4    cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm, 25 cm×8 cm, 25 cm×9 cm, 25    cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1 cm, 30 cm×2 cm, 30 cm×3    cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7 cm, 30 cm×8 cm, 30    cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40 cm×1 cm, 40 cm×2    cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40 cm×7 cm, 40    cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm, 50 cm×1    cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm, 50    cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50    cm×20 cm.-   312. The container according to item 273, wherein the bottom of the    inner cavity is formed as a square with dimensions of between 1 cm²    to 500 cm², such as 1 cm² to 5 cm², for example 5 cm² to 10 cm²,    such as 10 cm² to 20 cm², for example 20 cm² to 30 cm², such as 30    cm² to 40 cm², for example 40 cm² to 50 cm², such as 50 cm² to 60    cm², for example 60 cm² to 70 cm², such as 70 cm² to 80 cm², for    example 80 cm² to 90 cm², such as 90 cm² to 100 cm², for example 100    cm² to 110 cm², such as 110 cm² to 120 cm², for example 120 cm² to    130 cm², such as 130 cm² to 140 cm², for example 140 cm² to 150 cm²,    such as 150 cm² to 160 cm², for example 160 cm² to 170 cm², such as    170 cm² to 180 cm², for example 180 cm² to 190 cm², such as 190 cm²    to 200 cm², for example 200 cm² to 210 cm², such as 210 cm² to 220    cm², for example 220 cm² to 230 cm², such as 230 cm² to 240 cm², for    example 240 cm² to 250 cm², such as 250 cm² to 260 cm², for example    260 cm² to 270 cm², such as 270 cm² to 280 cm², for example 280 cm²    to 290 cm², such as 290 cm² to 300 cm², for example 300 cm² to 320    cm², such as 320 cm² to 340 cm², for example 340 cm² to 360 cm²,    such as 360 cm² to 380 cm², for example 380 cm² to 400 cm², such as    400 cm² to 420 cm², for example 420 cm² to 440 cm², such as 440 cm²    to 460 cm², for example 460 cm² to 480 cm², such as 480 cm² to 500    cm².-   313. The container according to item 273, wherein the bottom is    formed to circumvent a matrix material shaped as a square with one    of the dimensions selected from the group consisting of 1 cm×1 cm, 1    cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1 cm×5 cm, 1 cm×6 cm, 1 cm×7 cm, 1    cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1 cm×15 cm, 1 cm×20 cm, 2 cm×1 cm, 2    cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2 cm×5 cm, 2 cm×6 cm, 2 cm×7 cm, 2    cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2 cm×15 cm, 2 cm×20 cm, 3 cm×1 cm, 3    cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3 cm×5 cm, 3 cm×6 cm, 3 cm×7 cm, 3    cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3 cm×15 cm, 3 cm×20 cm, 4 cm×1 cm, 4    cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4 cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4    cm×8 cm, 4 cm×9 cm, 4 cm×10 cm, 4 cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5    cm×2 cm, 5 cm×3 cm, 5 cm×4 cm, 5 cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5    cm×8 cm, 5 cm×9 cm, 5 cm×10 cm, 5 cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6    cm×2 cm, 6 cm×3 cm, 6 cm×4 cm, 6 cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6    cm×8 cm, 6 cm×9 cm, 6 cm×10 cm, 6 cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7    cm×2 cm, 7 cm×3 cm, 7 cm×4 cm, 7 cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7    cm×8 cm, 7 cm×9 cm, 7 cm×10 cm, 7 cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8    cm×2 cm, 8 cm×3 cm, 8 cm×4 cm, 8 cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8    cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8 cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9    cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9 cm×5 cm, 9 cm×6 cm, 9 cm×7 cm, 9    cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9 cm×15 cm, 9 cm×20 cm, 10 cm×1 cm,    10 cm×2 cm, 10 cm×3 cm, 10 cm×4 cm, 10 cm×5 cm, 10 cm×6 cm, 10 cm×7    cm, 10 cm×8 cm, 10 cm×9 cm, 10 cm×10 cm, 10 cm×15 cm, 10 cm×20 cm,    11 cm×1 cm, 11 cm×2 cm, 11 cm×3 cm, 11 cm×4 cm, 11 cm×5 cm, 11 cm×6    cm, 11 cm×7 cm, 11 cm×8 cm, 11 cm×9 cm, 11 cm×10 cm, 11 cm×15 cm, 11    cm×20 cm, 12 cm×1 cm, 12 cm×2 cm, 12 cm×3 cm, 12 cm×4 cm, 12 cm×5    cm, 12 cm×6 cm, 12 cm×7 cm, 12 cm×8 cm, 12 cm×9 cm, 12 cm×10 cm, 12    cm×15 cm, 12 cm×20 cm, 13 cm×1 cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4    cm, 13 cm×5 cm, 13 cm×6 cm, 13 cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13    cm×10 cm, 13 cm×15 cm, 13 cm×20 cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3    cm, 14 cm×4 cm, 14 cm×5 cm, 14 cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14    cm×9 cm, 14 cm×10 cm, 14 cm×15 cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2    cm, 15 cm×3 cm, 15 cm×4 cm, 15 cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15    cm×8 cm, 15 cm×9 cm, 15 cm×10 cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1    cm, 16 cm×2 cm, 16 cm×3 cm, 16 cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16    cm×7 cm, 16 cm×8 cm, 16 cm×9 cm, 16 cm×10 cm, 16 cm×15 cm, 16 cm×20    cm, 17 cm×1 cm, 17 cm×2 cm, 17 cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17    cm×6 cm, 17 cm×7 cm, 17 cm×8 cm, 17 cm×9 cm, 17 cm×10 cm, 17 cm×15    cm, 17 cm×20 cm, 18 cm×1 cm, 18 cm×2 cm, 18 cm×3 cm, 18 cm×4 cm, 18    cm×5 cm, 18 cm×6 cm, 18 cm×7 cm, 18 cm×8 cm, 18 cm×9 cm, 18 cm×10    cm, 18 cm×15 cm, 18 cm×20 cm, 19 cm×1 cm, 19 cm×2 cm, 19 cm×3 cm, 19    cm×4 cm, 19 cm×5 cm, 19 cm×6 cm, 19 cm×7 cm, 19 cm×8 cm, 19 cm×9 cm,    19 cm×10 cm, 19 cm×15 cm, 19 cm×20 cm, 20 cm×1 cm, 20 cm×2 cm, 20    cm×3 cm, 20 cm×4 cm, 20 cm×5 cm, 20 cm×6 cm, 20 cm×7 cm, 20 cm×8 cm,    20 cm×9 cm, 20 cm×10 cm, 20 cm×15 cm, 20 cm×20 cm, 25 cm×1 cm, 25    cm×2 cm, 25 cm×3 cm, 25 cm×4 cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm,    25 cm×8 cm, 25 cm×9 cm, 25 cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30    cm×1 cm, 30 cm×2 cm, 30 cm×3 cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm,    30 cm×7 cm, 30 cm×8 cm, 30 cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30    cm×20 cm, 40 cm×1 cm, 40 cm×2 cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5    cm, 40 cm×6 cm, 40 cm×7 cm, 40 cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40    cm×15 cm, 40 cm×20 cm, 50 cm×1 cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4    cm, 50 cm×5 cm, 50 cm×6 cm, 50 cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50    cm×10 cm, 50 cm×15 cm, or 50 cm×20 cm.-   314. The container according to item 273, wherein the bottom is    formed to circumvent a matrix material shaped as a square with    dimensions of between 1 cm² to 500 cm², such as 1 cm² to 5 cm², for    example 5 cm² to 10 cm², such as 10 cm² to 20 cm², for example 20    cm² to 30 cm², such as 30 cm² to 40 cm², for example 40 cm² to 50    cm², such as 50 cm² to 60 cm², for example 60 cm² to 70 cm², such as    70 cm² to 80 cm², for example 80 cm² to 90 cm², such as 90 cm² to    100 cm², for example 100 cm² to 110 cm², such as 110 cm² to 120 cm²,    for example 120 cm² to 130 cm², such as 130 cm² to 140 cm², for    example 140 cm² to 150 cm², such as 150 cm² to 160 cm², for example    160 cm² to 170 cm², such as 170 cm² to 180 cm², for example 180 cm²    to 190 cm², such as 190 cm² to 200 cm², for example 200 cm² to 210    cm², such as 210 cm² to 220 cm², for example 220 cm² to 230 cm²,    such as 230 cm² to 240 cm², for example 240 cm² to 250 cm², such as    250 cm² to 260 cm², for example 260 cm² to 270 cm², such as 270 cm²    to 280 cm², for example 280 cm² to 290 cm², such as 290 cm² to 300    cm², for example 300 cm² to 320 cm², such as 320 cm² to 340 cm², for    example 340 cm² to 360 cm², such as 360 cm² to 380 cm², for example    380 cm² to 400 cm², such as 400 cm² to 420 cm², for example 420 cm²    to 440 cm², such as 440 cm² to 460 cm², for example 460 cm² to 480    cm², such as 480 cm² to 500 cm².-   315. The container according to item 273, wherein the bottom is    flat.-   316. The container according to item 273, wherein the bottom is    plane.-   317. The container according to item 273, wherein the bottom is    curved.-   318. The container according to item 273, wherein the bottom is    concave.-   319. The container according to item 273, wherein the bottom is    convex.-   320. The container according to item 273, wherein the bottom is not    plane.-   321. The container according to item 273, wherein the bottom is    irregular and/or non-uniform.-   322. The container according to item 273, wherein the bottom is    rough.-   323. The container according to item 273, wherein the height of the    sidewall(s) (from the bottom to the mark for maximum filling) is    selected from the groups consisting of 0 mm to 2 mm, 2 mm to 4 mm, 4    mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mm to 12 mm, 12 mm to 14    mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20 mm, 20 mm to 22 mm,    22 mm to 24 mm, 24 mm to 26 mm, 26 mm to 28 mm, 28 mm to 30 mm, 30    mm to 32 mm, 32 mm to 34 mm, 34 mm to 36 mm, 36 mm to 38 mm, 38 mm    to 40 mm, 40 mm to 42 mm, 42 mm to 44 mm, 44 mm to 46 mm, 46 mm to    48 mm or 48 mm to 50 mm.-   324. The container according to item 273, wherein the width of the    sidewall(s) is selected from the groups consisting of 0 mm to 2 mm,    2 mm to 4 mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10 mm to 12    mm, 12 mm to 14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm to 20 mm.-   325. The container according to item 273, wherein the height from    the bottom to the lid is selected from the groups consisting of 0 mm    to 2 mm, 2 mm to 4 mm, 4 mm to 6 mm, 6 mm to 8 mm, 8 mm to 10 mm, 10    mm to 12 mm, 12 mm to 14 mm, 14 mm to 16 mm, 16 mm to 18 mm, 18 mm    to 20 mm, 20 mm to 22 mm, 22 mm to 24 mm, 24 mm to 26 mm, 26 mm to    28 mm, 28 mm to 30 mm, 30 mm to 32 mm, 32 mm to 34 mm, 34 mm to 36    mm, 36 mm to 38 mm, 38 mm to 40 mm, 40 mm to 42 mm, 42 mm to 44 mm,    44 mm to 46 mm, 46 mm to 48 mm or 48 mm to 50 mm.-   326. The container according to item 273, wherein the sealing    surface for a lid is comprised in the upper portion of the one or    more sidewall(s).-   327. The container according to item 273, wherein the container    comprises a base.-   328. The container according to item 327, wherein the base of the    container is formed as a square.-   329. The container according to item 327, wherein the base of the    container is formed as a rectangle.-   330. The container according to item 327, wherein the base of the    container is formed as a triangle.-   331. The container according to item 327, wherein the base of the    container is formed as a circle.-   332. The container according to item 327, wherein the base of the    container is formed as an oval.-   333. The container according to item 327, wherein the base of the    container is formed as a square with dimensions selected from the    group consisting of 1 cm×1 cm, 1 cm×2 cm, 1 cm×3 cm, 1 cm×4 cm, 1    cm×5 cm, 1 cm×6 cm, 1 cm×7 cm, 1 cm×8 cm, 1 cm×9 cm, 1 cm×10 cm, 1    cm×15 cm, 1 cm×20 cm, 2 cm×1 cm, 2 cm×2 cm, 2 cm×3 cm, 2 cm×4 cm, 2    cm×5 cm, 2 cm×6 cm, 2 cm×7 cm, 2 cm×8 cm, 2 cm×9 cm, 2 cm×10 cm, 2    cm×15 cm, 2 cm×20 cm, 3 cm×1 cm, 3 cm×2 cm, 3 cm×3 cm, 3 cm×4 cm, 3    cm×5 cm, 3 cm×6 cm, 3 cm×7 cm, 3 cm×8 cm, 3 cm×9 cm, 3 cm×10 cm, 3    cm×15 cm, 3 cm×20 cm, 4 cm×1 cm, 4 cm×2 cm, 4 cm×3 cm, 4 cm×4 cm, 4    cm×5 cm, 4 cm×6 cm, 4 cm×7 cm, 4 cm×8 cm, 4 cm×9 cm, 4 cm×10 cm, 4    cm×15 cm, 4 cm×20 cm, 5 cm×1 cm, 5 cm×2 cm, 5 cm×3 cm, 5 cm×4 cm, 5    cm×5 cm, 5 cm×6 cm, 5 cm×7 cm, 5 cm×8 cm, 5 cm×9 cm, 5 cm×10 cm, 5    cm×15 cm, 5 cm×20 cm, 6 cm×1 cm, 6 cm×2 cm, 6 cm×3 cm, 6 cm×4 cm, 6    cm×5 cm, 6 cm×6 cm, 6 cm×7 cm, 6 cm×8 cm, 6 cm×9 cm, 6 cm×10 cm, 6    cm×15 cm, 6 cm×20 cm, 7 cm×1 cm, 7 cm×2 cm, 7 cm×3 cm, 7 cm×4 cm, 7    cm×5 cm, 7 cm×6 cm, 7 cm×7 cm, 7 cm×8 cm, 7 cm×9 cm, 7 cm×10 cm, 7    cm×15 cm, 7 cm×20 cm, 8 cm×1 cm, 8 cm×2 cm, 8 cm×3 cm, 8 cm×4 cm, 8    cm×5 cm, 8 cm×6 cm, 8 cm×7 cm, 8 cm×8 cm, 8 cm×9 cm, 8 cm×10 cm, 8    cm×15 cm, 8 cm×20 cm, 9 cm×1 cm, 9 cm×2 cm, 9 cm×3 cm, 9 cm×4 cm, 9    cm×5 cm, 9 cm×6 cm, 9 cm×7 cm, 9 cm×8 cm, 9 cm×9 cm, 9 cm×10 cm, 9    cm×15 cm, 9 cm×20 cm, 10 cm×1 cm, 10 cm×2 cm, 10 cm×3 cm, 10 cm×4    cm, 10 cm×5 cm, 10 cm×6 cm, 10 cm×7 cm, 10 cm×8 cm, 10 cm×9 cm, 10    cm×10 cm, 10 cm×15 cm, 10 cm×20 cm, 11 cm×1 cm, 11 cm×2 cm, 11 cm×3    cm, 11 cm×4 cm, 11 cm×5 cm, 11 cm×6 cm, 11 cm×7 cm, 11 cm×8 cm, 11    cm×9 cm, 11 cm×10 cm, 11 cm×15 cm, 11 cm×20 cm, 12 cm×1 cm, 12 cm×2    cm, 12 cm×3 cm, 12 cm×4 cm, 12 cm×5 cm, 12 cm×6 cm, 12 cm×7 cm, 12    cm×8 cm, 12 cm×9 cm, 12 cm×10 cm, 12 cm×15 cm, 12 cm×20 cm, 13 cm×1    cm, 13 cm×2 cm, 13 cm×3 cm, 13 cm×4 cm, 13 cm×5 cm, 13 cm×6 cm, 13    cm×7 cm, 13 cm×8 cm, 13 cm×9 cm, 13 cm×10 cm, 13 cm×15 cm, 13 cm×20    cm, 14 cm×1 cm, 14 cm×2 cm, 14 cm×3 cm, 14 cm×4 cm, 14 cm×5 cm, 14    cm×6 cm, 14 cm×7 cm, 14 cm×8 cm, 14 cm×9 cm, 14 cm×10 cm, 14 cm×15    cm, 14 cm×20 cm, 15 cm×1 cm, 15 cm×2 cm, 15 cm×3 cm, 15 cm×4 cm, 15    cm×5 cm, 15 cm×6 cm, 15 cm×7 cm, 15 cm×8 cm, 15 cm×9 cm, 15 cm×10    cm, 15 cm×15 cm, 15 cm×20 cm, 16 cm×1 cm, 16 cm×2 cm, 16 cm×3 cm, 16    cm×4 cm, 16 cm×5 cm, 16 cm×6 cm, 16 cm×7 cm, 16 cm×8 cm, 16 cm×9 cm,    16 cm×10 cm, 16 cm×15 cm, 16 cm×20 cm, 17 cm×1 cm, 17 cm×2 cm, 17    cm×3 cm, 17 cm×4 cm, 17 cm×5 cm, 17 cm×6 cm, 17 cm×7 cm, 17 cm×8 cm,    17 cm×9 cm, 17 cm×10 cm, 17 cm×15 cm, 17 cm×20 cm, 18 cm×1 cm, 18    cm×2 cm, 18 cm×3 cm, 18 cm×4 cm, 18 cm×5 cm, 18 cm×6 cm, 18 cm×7 cm,    18 cm×8 cm, 18 cm×9 cm, 18 cm×10 cm, 18 cm×15 cm, 18 cm×20 cm, 19    cm×1 cm, 19 cm×2 cm, 19 cm×3 cm, 19 cm×4 cm, 19 cm×5 cm, 19 cm×6 cm,    19 cm×7 cm, 19 cm×8 cm, 19 cm×9 cm, 19 cm×10 cm, 19 cm×15 cm, 19    cm×20 cm, 20 cm×1 cm, 20 cm×2 cm, 20 cm×3 cm, 20 cm×4 cm, 20 cm×5    cm, 20 cm×6 cm, 20 cm×7 cm, 20 cm×8 cm, 20 cm×9 cm, 20 cm×10 cm, 20    cm×15 cm, 20 cm×20 cm, 25 cm×1 cm, 25 cm×2 cm, 25 cm×3 cm, 25 cm×4    cm, 25 cm×5 cm, 25 cm×6 cm, 25 cm×7 cm, 25 cm×8 cm, 25 cm×9 cm, 25    cm×10 cm, 25 cm×15 cm, 25 cm×20 cm, 30 cm×1 cm, 30 cm×2 cm, 30 cm×3    cm, 30 cm×4 cm, 30 cm×5 cm, 30 cm×6 cm, 30 cm×7 cm, 30 cm×8 cm, 30    cm×9 cm, 30 cm×10 cm, 30 cm×15 cm, 30 cm×20 cm, 40 cm×1 cm, 40 cm×2    cm, 40 cm×3 cm, 40 cm×4 cm, 40 cm×5 cm, 40 cm×6 cm, 40 cm×7 cm, 40    cm×8 cm, 40 cm×9 cm, 40 cm×10 cm, 40 cm×15 cm, 40 cm×20 cm, 50 cm×1    cm, 50 cm×2 cm, 50 cm×3 cm, 50 cm×4 cm, 50 cm×5 cm, 50 cm×6 cm, 50    cm×7 cm, 50 cm×8 cm, 50 cm×9 cm, 50 cm×10 cm, 50 cm×15 cm, or 50    cm×20 cm.-   334. The container according to item 327, wherein the base of the    container is formed as a square with dimensions of between 1 cm² to    500 cm², such as 1 cm² to 5 cm², for example 5 cm² to 10 cm², such    as 10 cm² to 20 cm², for example 20 cm² to 30 cm², such as 30 cm² to    40 cm², for example 40 cm² to 50 cm², such as 50 cm² to 60 cm², for    example 60 cm² to 70 cm², such as 70 cm² to 80 cm², for example 80    cm² to 90 cm², such as 90 cm² to 100 cm², for example 100 cm² to 110    cm², such as 110 cm² to 120 cm², for example 120 cm² to 130 cm²,    such as 130 cm² to 140 cm², for example 140 cm² to 150 cm², such as    150 cm² to 160 cm², for example 160 cm² to 170 cm², such as 170 cm²    to 180 cm², for example 180 cm² to 190 cm², such as 190 cm² to 200    cm², for example 200 cm² to 210 cm², such as 210 cm² to 220 cm², for    example 220 cm² to 230 cm², such as 230 cm² to 240 cm², for example    240 cm² to 250 cm², such as 250 cm² to 260 cm², for example 260 cm²    to 270 cm², such as 270 cm² to 280 cm², for example 280 cm² to 290    cm², such as 290 cm² to 300 cm², for example 300 cm² to 320 cm²,    such as 320 cm² to 340 cm², for example 340 cm² to 360 cm², such as    360 cm² to 380 cm², for example 380 cm² to 400 cm², such as 400 cm²    to 420 cm², for example 420 cm² to 440 cm², such as 440 cm² to 460    cm², for example 460 cm² to 480 cm², such as 480 cm² to 500 cm².-   335. The container according to item 327, wherein the base is    contacting the one or more sidewall(s) at one or more points, such    as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.-   336. The container according to item 327, wherein the base is    contacting the bottom at one or more points, such as 1, 2, 3, 4, 5,    6, 7, 8, 9 or 10 points.-   337. The container according to item 327, wherein the base comprises    a flat bottom.-   338. The container according to item 327, wherein the base comprises    one or more handles.-   339. The container according to item 327, wherein the base comprises    one or more recesses or indentations.-   340. The container according to item 327, wherein the base comprises    the sealing surface for a lid.-   341. The container according to item 327, wherein the base comprises    a flat portion.-   342. The container according to item 327, wherein the base comprises    a plane portion.-   343. The container according to item 327, wherein the base comprises    a curved portion.-   344. The container according to item 327, wherein the base comprises    a concave portion.-   345. The container according to item 327, wherein the base comprises    a convex portion.-   346. The container according to item 327, wherein the base is not    plane.-   347. The container according to item 327, wherein the base is    irregular and/or non-uniform.-   348. The container according to item 327, wherein the base is rough.-   349. The container according to item 327, wherein the base comprises    one or more extended base plate(s).-   350. The container according to item 327, wherein the base comprises    a vertical portion.-   351. The container according to item 327, wherein the base comprises    a horizontal portion.-   352. The container according to item 273, wherein the container is    made of or comprises plastic.-   353. The container according to item 273, wherein the container is    made of or comprises flexible plastic.-   354. The container according to item 273, wherein the container is    made of or comprises rigid plastic.-   355. The container according to item 273, wherein the container is    made of or comprises transparent plastic.-   356. The container according to item 273, wherein the container is    made of or comprises a medical grade polymer such as plastic.-   357. The container according to item 273, wherein the container is    made of or comprises one or more of the materials selected from the    group consisting of Biodegradable plastic, Bioplastics obtained from    biomass e.g. from pea starch or from biopetroleum, Polypropylene    (PP), Polystyrene (PS), High impact polystyrene (HIPS),    Acrylonitrile butadiene styrene (ABS), Polyethylene terephthalate    (PET), Amorphous PET (APET), Polyester (PES), Fibers, textiles,    Polyamides (PA), (Nylons), Poly(vinyl chloride) (PVC), Polyurethanes    (PU), Polycarbonate (PC), Polyvinylidene chloride (PVDC) (Saran),    Polyvinylidene Fluoride (PVDF), Polyethylene (PE), Polymethyl    methacrylate (PMMA), Polytetrafluoroethylene (PTFE) (trade name    Teflon), Fluorinated ethylene propylene (FEP), Polyetheretherketone    (PEEK) (Polyetherketone), Polyetherimide (PEI) (Ultem), Phenolics    (PF), (phenol formaldehydes), Perfluoroalkoxy (PFA), Poly(methyl    methacrylate) (PMMA), Urea-formaldehyde (UF), Melamine formaldehyde    (MF), Polylactic acid and Plastarch material or any mixture thereof-   358. The container according to item 273, wherein the container is    made of or comprises one or more materials selected from the group    consisting of TECAFORM™ AH MT, CELCON® (Acetal Copolymer), RADEL®,    TECASON™ P XRO (Polyphenylsulfone, also Radio Opacifer), UDEL®    Polysulfone, ULTEM® (Polyetherimide), UHMW Lot Controlled, LENNITE®    UHME-PE, TECANAT™ PC (USP Class VI Polycarbonate Rod), ZELUX® GS    (Gamma Stabilized Polycarbonate), ACRYLIC (Medical grade Cast    Acrylic), TECAMAX™ SRP (Ultra High Performance Thermoplastic),    TECAPRO™ MT (Polypropylene Heat Stabilized), TECAPEEK™ MT (USP Class    VI compliant), TECAFORM™ AH SAN, ANTIMICROBIAL filled plastics,    TECASON™ P XRO (Biocompatible Radio Opacifer PPSU), TECAPEEK™    CLASSIX, POLYSULFONE® (Medical grade), TECANYL™ (Medical grade    Noryl®), TYGON® (Medical grade Tubing), TEXOLON™ Medical Grade PTFE    (USP CLASS VI), PROPYLUX HS and HS2, ABS (FDA Approved Medical    Grades), TOPAS® (Medical grade), and other Medical Grade/FDA    approved plastic products.-   359. The container according to item 273, wherein the container is    made of or comprises one or more polymers of high molecular weight.-   360. The container according to item 359, wherein the container is    made of or comprises one or more polymers and/or plastics with a    molecular weight in the range from 10,000 to 1,000,000 Da, such as    from 10,000 to 50,000 Da, for example 50,000 to 100,000 Da, such as    from 100,000 to 150,000 Da, for example 150,000 to 200,000 Da, such    as from 200,000 to 250,000 Da, for example 250,000 to 238,000 Da,    such as from 238,000 to 350,000 Da, for example 350,000 to 400,000    Da, such as from 400,000 to 450,000 Da, for example 450,000 to    500,000 Da, such as from 500,000 to 550,000 Da, for example 550,000    to 600,000 Da, such as from 600,000 to 650,000 Da, for example    650,000 to 700,000 Da, such as from 700,000 to 750,000 Da, for    example 750,000 to 800,000 Da, such as from 800,000 to 850,000 Da,    for example 850,000 to 900,000 Da, such as from 900,000 to 950,000    Da, for example 950,000 to 1,000,000 Da.-   361. The container according to item 273, wherein the container is    made of or comprises one or more types of Rubber.-   362. The container according to item 273, wherein the container is    made of or comprises one or more types of Cellulose-based plastics.-   363. The container according to item 273, wherein the container is    made of or comprises one or more types of Bakelite.-   364. The container according to item 273, wherein the container is    made of or comprises one or more types of Polystyrene.-   365. The container according to item 273, wherein the container is    made of or comprises one or more types of PVC.-   366. The container according to item 273, wherein the container is    made of or comprises one or more types of Nylon.-   367. The container according to item 273, wherein the container is    made of or comprises one or more types of Synthetic rubber.-   368. The container according to item 273, wherein the container is    made of or comprises one or more acrylics.-   369. The container according to item 273, wherein the container is    made of or comprises one or more polyesters.-   370. The container according to item 273, wherein the container is    made of or comprises one or more silicones.-   371. The container according to item 273, wherein the container is    made of or comprises one or more polyurethanes.-   372. The container according to item 273, wherein the container is    made of or comprises one or more halogenated plastics.-   373. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises plastic.-   374. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises flexible plastic.-   375. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises rigid plastic.-   376. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises transparent plastic.-   377. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises medical grade    polymer such as plastic.-   378. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    materials selected from the group consisting of Biodegradable    plastic, Bioplastics obtained from biomass e.g. from pea starch or    from biopetroleum, Polypropylene (PP), Polystyrene (PS), High impact    polystyrene (HIPS), Acrylonitrile butadiene styrene (ABS),    Polyethylene terephthalate (PET), Amorphous PET (APET), Polyester    (PES), Fibers, textiles, Polyamides (PA), (Nylons), Poly(vinyl    chloride) (PVC), Polyurethanes (PU), Polycarbonate (PC),    Polyvinylidene chloride (PVDC) (Saran), Polyvinylidene Fluoride    (PVDF), Polyethylene (PE), Polymethyl methacrylate (PMMA),    Polytetrafluoroethylene (PTFE) (trade name Teflon), Fluorinated    ethylene propylene (FEP), Polyetheretherketone (PEEK)    (Polyetherketone), Polyetherimide (PEI) (Ultem), Phenolics (PF),    (phenol formaldehydes), Perfluoroalkoxy (PFA), Poly(methyl    methacrylate) (PMMA), Urea-formaldehyde (UF), Melamine formaldehyde    (MF), Polylactic acid and Plastarch material or any mixture thereof-   379. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more of the    materials selected from the group consisting of TECAFORM™ AH MT,    CELCON® (Acetal Copolymer), RADEL®, TECASON™ P XRO    (Polyphenylsulfone, also Radio Opacifer), UDEL® Polysulfone, ULTEM®    (Polyetherimide), UHMW Lot Controlled, LENNITE® UHME-PE, TECANAT™ PC    (USP Class VI Polycarbonate Rod), ZELUX® GS (Gamma Stabilized    Polycarbonate), ACRYLIC (Medical grade Cast Acrylic), TECAMAX™ SRP    (Ultra High Performance Thermoplastic), TECAPRO™ MT (Polypropylene    Heat Stabilized), TECAPEEK™ MT (USP Class VI compliant), TECAFORM™    AFI SAN, ANTIMICROBIAL filled plastics, TECASON™ P XRO    (Biocompatible Radio Opacifer PPSU), TECAPEEK™ CLASSIX, POLYSULFONE®    (Medical grade), TECANYL™ (Medical grade Noryl®), TYGON® (Medical    grade Tubing), TEXOION™ Medical Grade PTFE (USP CLASS VI), PROPYLUX    HS and HS2, ABS (FDA Approved Medical Grades), TOPAS® (Medical    grade), and other Medical Grade/FDA approved plastic products.-   380. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more polymers    of high molecular weight.-   381. The container according to item 380, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more polymers    and/or plastics with a molecular weight in the range from 10,000 to    1,000,000 Da, such as from 10,000 to 50,000 Da, for example 50,000    to 100,000 Da, such as from 100,000 to 150,000 Da, for example    150,000 to 200,000 Da, such as from 200,000 to 250,000 Da, for    example 250,000 to 238,000 Da, such as from 238,000 to 350,000 Da,    for example 350,000 to 400,000 Da, such as from 400,000 to 450,000    Da, for example 450,000 to 500,000 Da, such as from 500,000 to    550,000 Da, for example 550,000 to 600,000 Da, such as from 600,000    to 650,000 Da, for example 650,000 to 700,000 Da, such as from    700,000 to 750,000 Da, for example 750,000 to 800,000 Da, such as    from 800,000 to 850,000 Da, for example 850,000 to 900,000 Da, such    as from 900,000 to 950,000 Da, for example 950,000 to 1,000,000 Da.-   382. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Rubber.-   383. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Cellulose-based plastics.-   384. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Bakelite.-   385. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Polystyrene.-   386. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    PVC.-   387. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Nylon.-   388. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more types of    Synthetic rubber.-   389. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    acrylics.-   390. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    polyesters.-   391. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    silicones.-   392. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    polyurethanes.-   393. The container according to item 273, wherein the one or more    sidewalls and/or bottom is made of or comprises one or more    halogenated plastics.-   394. The container according to item 273, wherein the lid is made of    or comprises a peelable material.-   395. The container according to item 394, wherein the peelable    material is selected from the group consisting of polyethylene (PE),    thermoplastic elastomer, thermoset elastomer, Tyvek, Teslin, paper,    plastic foil or metal foil.-   396. The container according to item 394, wherein the lid is    reinforced with a coating, such as a synthetic coating.-   397. The container according to item 396, wherein the synthetic    coating is selected from the group consisting of Perfluorooctanoic    acid (PFOA), hydrocarbon based petrochemicals, zein or others.-   398. The container according to item 273, wherein the lid is made of    or comprises plastic.-   399. The container according to item 273, wherein the lid is made of    or comprises flexible plastic.-   400. The container according to item 273, wherein the lid is made of    or comprises rigid plastic.-   401. The container according to item 273, wherein the lid is made of    or comprises transparent plastic.-   402. The container according to item 273, wherein the lid is made of    or comprises medical grade polymer such as plastic.-   403. The container according to item 273, wherein the lid is made of    or comprises one or more materials selected from the group    consisting of Biodegradable plastic, Bioplastics obtained from    biomass e.g. from pea starch or from biopetroleum, Polypropylene    (PP), Polystyrene (PS), High impact polystyrene (HIPS),    Acrylonitrile butadiene styrene (ABS), Polyethylene terephthalate    (PET), Amorphous PET (APET), Polyester (PES), Fibers, textiles,    Polyamides (PA), (Nylons), Poly(vinyl chloride) (PVC), Polyurethanes    (PU), Polycarbonate (PC), Polyvinylidene chloride (PVDC) (Saran),    Polyvinylidene Fluoride (PVDF), Polyethylene (PE), Polymethyl    methacrylate (PMMA), Polytetrafluoroethylene (PTFE) (trade name    Teflon), Fluorinated ethylene propylene (FEP), Polyetheretherketone    (PEEK) (Polyetherketone), Polyetherimide (PEI) (Ultem), Phenolics    (PF), (phenol formaldehydes), Perfluoroalkoxy (PFA), Poly(methyl    methacrylate) (PMMA), Urea-formaldehyde (UF), Melamine formaldehyde    (MF), Polylactic acid and Plastarch material or any mixture thereof-   404. The container according to item 273, wherein the lid is made of    or comprises one or more of the materials selected from the group    consisting of TECAFORM™ AH MT, CELCON® (Acetal Copolymer), RADEL®,    TECASON™ P XRO (Polyphenylsulfone, also Radio Opacifer), UDEL®    Polysulfone, ULTEM® (Polyetherimide), UHMW Lot Controlled, LENNITE®    UHME-PE, TECANAT™ PC (USP Class VI Polycarbonate Rod), ZELUX® GS    (Gamma Stabilized Polycarbonate), ACRYLIC (Medical grade Cast    Acrylic), TECAMAX™ SRP (Ultra High Performance Thermoplastic),    TECAPRO™ MT (Polypropylene Heat Stabilized), TECAPEEK™ MT (USP Class    VI compliant), TECAFORM™ AH SAN, ANTIMICROBIAL filled plastics,    TECASON™ P XRO (Biocompatible Radio Opacifer PPSU), TECAPEEK™    CLASSIX, POLYSULFONE® (Medical grade), TECANYL™ (Medical grade    Noryl®), TYGON® (Medical grade Tubing), TEXOLON™ Medical Grade PTFE    (USP CLASS VI), PROPYLUX HS and HS2, ABS (FDA Approved Medical    Grades), TOPAS® (Medical grade), and other Medical Grade/FDA    approved plastic products.-   405. The container according to item 273, wherein the lid is made of    or comprises one or more polymers of high molecular weight.-   406. The container according to item 405, wherein the lid is made of    or comprises one or more polymers and/or plastics with a molecular    weight in the range from 10,000 to 1,000,000 Da, such as from 10,000    to 50,000 Da, for example 50,000 to 100,000 Da, such as from 100,000    to 150,000 Da, for example 150,000 to 200,000 Da, such as from    200,000 to 250,000 Da, for example 250,000 to 238,000 Da, such as    from 238,000 to 350,000 Da, for example 350,000 to 400,000 Da, such    as from 400,000 to 450,000 Da, for example 450,000 to 500,000 Da,    such as from 500,000 to 550,000 Da, for example 550,000 to 600,000    Da, such as from 600,000 to 650,000 Da, for example 650,000 to    700,000 Da, such as from 700,000 to 750,000 Da, for example 750,000    to 800,000 Da, such as from 800,000 to 850,000 Da, for example    850,000 to 900,000 Da, such as from 900,000 to 950,000 Da, for    example 950,000 to 1,000,000 Da.-   407. The container according to item 273, wherein the lid is made of    or comprises one or more types of Rubber.-   408. The container according to item 273, wherein the lid is made of    or comprises one or more types of Cellulose-based plastics.-   409. The container according to item 273, wherein the lid is made of    or comprises one or more types of Bakelite.-   410. The container according to item 273, wherein the lid is made of    or comprises one or more types of Polystyrene.-   411. The container according to item 273, wherein the lid is made of    or comprises one or more types of PVC.-   412. The container according to item 273, wherein the lid is made of    or comprises one or more types of Nylon.-   413. The container according to item 273, wherein the lid is made of    or comprises one or more types of Synthetic rubber.-   414. The container according to item 273, wherein the lid is made of    or comprises one or more acrylics.-   415. The container according to item 273, wherein the lid is made of    or comprises one or more polyesters.-   416. The container according to item 273, wherein the lid is made of    or comprises one or more silicones.-   417. The container according to item 273, wherein the lid is made of    or comprises one or more polyurethanes.-   418. The container according to item 273, wherein the lid is made of    or comprises one or more halogenated plastics.-   419. The container according to item 327, wherein the base is made    of or comprises plastic.-   420. The container according to item 327, wherein the base is made    of or comprises flexible plastic.-   421. The container according to item 327, wherein the base is made    of or comprises transparent plastic.-   422. The container according to item 327, wherein the base is made    of or comprises medical grade polymer such as plastic.-   423. The container according to item 327, wherein the base is made    of or comprises one or more materials selected from the group    consisting of TECAFORM™ AH MT, CELCON® (Acetal Copolymer), RADEL®,    TECASON™ P XRO (Polyphenylsulfone, also Radio Opacifer), UDEL®    Polysulfone, ULTEM® (Polyetherimide), UHMW Lot Controlled, LENNITE®    UI TECANAT™ PC (USP Class VI Polycarbonate Rod), ZELUX® GS (Gamma    Stabilized Polycarbonate), ACRYLIC (Medical grade Cast Acrylic),    TECAMAX™ SRP (Ultra High Performance Thermoplastic), TECAPRO™ MT    (Polypropylene Heat Stabilized), TECAPEEK™ MT (USP Class VI    compliant), TECAFORM™ AH SAN, ANTIMICROBIAL filled plastics,    TECASON™ P XRO (Biocompatible Radio Opacifer PPSU), TECAPEEK™    CLASSIX, POLYSULFONE® (Medical grade), TECANYL™ (Medical grade    Noryl®), TYGON® (Medical grade Tubing), TEXOLON™ Medical Grade PTFE    (USP CLASS VI), PROPYLUX HS and HS2, ABS (FDA Approved Medical    Grades), TOPAS® (Medical grade), and other Medical Grade/FDA    approved plastic products.-   424. The container according to item 327, wherein the base is made    of or comprises one or more of the materials selected from the group    consisting of Biodegradable plastic, Bioplastics obtained from    biomass e.g. from pea starch or from biopetroleum, Polypropylene    (PP), Polystyrene (PS), High impact polystyrene (HIPS),    Acrylonitrile butadiene styrene (ABS), Polyethylene terephthalate    (PET), Amorphous PET (APET), Polyester (PES), Fibers, textiles,    Polyamides (PA), (Nylons), Poly(vinyl chloride) (PVC), Polyurethanes    (PU), Polycarbonate (PC), Polyvinylidene chloride (PVDC) (Saran),    Polyvinylidene Fluoride (PVDF), Polyethylene (PE), Polymethyl    methacrylate (PMMA), Polytetrafluoroethylene (PTFE) (trade name    Teflon), Fluorinated ethylene propylene (FEP), Polyetheretherketone    (PEEK) (Polyetherketone), Polyetherimide (PEI) (Ultem), Phenolics    (PF), (phenol formaldehydes), Perfluoroalkoxy (PFA), Poly(methyl    methacrylate) (PMMA), Urea-formaldehyde (UF), Melamine formaldehyde    (MF), Polylactic acid and Plastarch material or any mixture thereof.-   425. The container according to item 327, wherein the base is made    of or comprises one or more polymers of high molecular weight.-   426. The container according to item 425, wherein the base is made    of or comprises one or more polymers and/or plastics with a    molecular weight in the range from 10,000 to 1,000,000 Da, such as    from 10,000 to 50,000 Da, for example 50,000 to 100,000 Da, such as    from 100,000 to 150,000 Da, for example 150,000 to 200,000 Da, such    as from 200,000 to 250,000 Da, for example 250,000 to 238,000 Da,    such as from 238,000 to 350,000 Da, for example 350,000 to 400,000    Da, such as from 400,000 to 450,000 Da, for example 450,000 to    500,000 Da, such as from 500,000 to 550,000 Da, for example 550,000    to 600,000 Da, such as from 600,000 to 650,000 Da, for example    650,000 to 700,000 Da, such as from 700,000 to 750,000 Da, for    example 750,000 to 800,000 Da, such as from 800,000 to 850,000 Da,    for example 850,000 to 900,000 Da, such as from 900,000 to 950,000    Da, for example 950,000 to 1,000,000 Da.-   427. The container according to item 327, wherein the base is made    of or comprises one or more types of Rubber.-   428. The container according to item 327, wherein the base is made    of or comprises one or more types of Cellulose-based plastics.-   429. The container according to item 327, wherein the base is made    of or comprises one or more types of Bakelite.-   430. The container according to item 327, wherein the base is made    of or comprises one or more types of Polystyrene.-   431. The container according to item 327, wherein the base is made    of or comprises one or more types of PVC.-   432. The container according to item 327, wherein the base is made    of or comprises one or more types of Nylon.-   433. The container according to item 327, wherein the base is made    of or comprises one or more types of Synthetic rubber.-   434. The container according to item 327, wherein the base is made    of or comprises one or more acrylics.-   435. The container according to item 327, wherein the base is made    of or comprises one or more polyesters.-   436. The container according to item 327, wherein the base is made    of or comprises one or more silicones.-   437. The container according to item 327, wherein the base is made    of or comprises one or more polyurethanes.-   438. The container according to item 327, wherein the base is made    of or comprises one or more halogenated plastics.-   439. The container according to item 273, wherein the container    comprises an inner cavity where the maximum volume of liquid that    can be added to the inner cavity comprising a matrix material is in    range of from 5% to 50% of the volume of the matrix material such as    from 5% to 6%, for example from 6% to 7%, such as from 7% to 8%, for    example from 8% to 9%, such as from 9% to 10%, for example from 10%    to 11%, such as from 11% to 12%, for example from 12% to 13%, such    as from 13% to 14%, for example from 14% to 15%, such as from 15% to    16%, for example from 16% to 17%, such as from 17% to 18%, for    example from 18% to 19%, such as from 19% to 20%, for example from    20% to 21%, such as from 21% to 22%, for example from 22% to 23%,    such as from 23% to 24%, for example from 24% to 25%, such as from    25% to 26%, for example from 26% to 27%, such as from 27% to 28%,    for example from 28% to 29%, such as from 29% to 30%, for example    from 30% to 31%, such as from 31% to 32%, for example from 32% to    33%, such as from 33% to 34%, for example from 34% to 35%, such as    from 35% to 36%, for example from 36% to 37%, such as from 37% to    38%, for example from 38% to 39%, such as from 39% to 40%, for    example from 40% to 41%, such as from 41% to 42%, for example from    42% to 43%, such as from 43% to 44%, for example from 44% to 45%,    such as from 45% to 46%, for example from 46% to 47%, such as from    47% to 48%, for example from 48% to 49%, or such as from 49% to 50%.-   440. A kit of parts comprising a matrix material according to any of    the items 1 to 138, 144 to 235 and 241 to 267 and at least one    additional component.-   441. The kit of part according to item 440, wherein the one    additional component is the container according to items 273 to 439.-   442. A kit of parts comprising the matrix material according to any    of the items 1 to 138 and the container according to items 273 to    439.-   443. A method for making the kit of parts according to any of items    440 to 442.-   444. Use of the kit of parts according to any of items 440 to 442 in    a method for promoting wound healing in an individual in need    thereof.-   445. Use of the kit of parts according to any of items 440 to 442 in    a method for promoting hemostasis in an individual in need thereof.-   446. A method for use of the kit of parts according to any of items    440 to 442 comprising the steps of    -   i) storing of the matrix material in the container    -   ii) opening of said container    -   iii) optional addition of liquid/moisture to container        comprising the matrix material    -   iv) transfer of said matrix material to an individual in need        thereof    -   to promote wound healing in the individual in need thereof.-   447. A method for use of the kit of parts according to any of items    440 to 442 comprising the steps of    -   i) storing of the matrix material in the container    -   ii) opening of said container    -   iii) optional addition of liquid/moisture to container        comprising the matrix material    -   iv) transfer of said matrix material to an individual in need        thereof    -   to promote hemostasis in the individual in need thereof.-   448. The method according to any of items 446 or 447, wherein the    addition of liquid/moisture comprises addition of a volume of    liquid/moisture in range of from 5% to 50% of the volume of the    matrix material such as from 5% to 6%, for example from 6% to 7%,    such as from 7% to 8%, for example from 8% to 9%, such as from 9% to    10%, for example from 10% to 11%, such as from 11% to 12%, for    example from 12% to 13%, such as from 13% to 14%, for example from    14% to 15%, such as from 15% to 16%, for example from 16% to 17%,    such as from 17% to 18%, for example from 18% to 19%, such as from    19% to 20%, for example from 20% to 21%, such as from 21% to 22%,    for example from 22% to 23%, such as from 23% to 24%, for example    from 24% to 25%, such as from 25% to 26%, for example from 26% to    27%, such as from 27% to 28%, for example from 28% to 29%, such as    from 29% to 30%, for example from 30% to 31%, such as from 31% to    32%, for example from 32% to 33%, such as from 33% to 34%, for    example from 34% to 35%, such as from 35% to 36%, for example from    36% to 37%, such as from 37% to 38%, for example from 38% to 39%,    such as from 39% to 40%, for example from 40% to 41%, such as from    41% to 42%, for example from 42% to 43%, such as from 43% to 44%,    for example from 44% to 45%, such as from 45% to 46%, for example    from 46% to 47%, such as from 47% to 48%, for example from 48% to    49%, or such as from 49% to 50%.-   449. The method according to any of items 446 or 447, wherein the    liquid/moisture added to the container comprising the matrix    material is a sterile saline solution.-   450. The method according to item 449, wherein the sterile saline    solution is a sterile sodium chloride solution.-   451. The method according to item 450, wherein the sterile sodium    chloride solution is a sterile sodium chloride 0.9% solution.-   452. The method according to any of items 446 or 447, wherein the    liquid/moisture added to the container comprising the matrix    material is sterile water.

1-44. (canceled)
 45. A hemostatic matrix material comprising a surface and a plurality of open and interconnected cells, said matrix material comprising gelatin or collagen, wherein the surface of said matrix material comprises a hemostatic composition distributed in a uniform manner.
 46. The matrix material according to claim 45, wherein the surface of the matrix material contains less than 100 IU/cm² of the hemostatic composition.
 47. The matrix material according to claim 45, wherein the surface of the matrix material contains between 0.5 and 50 IU/cm² of the hemostatic composition.
 48. The matrix material according to claim 45, wherein the distribution of the hemostatic composition is such that any two area units differ in the concentration of the hemostatic composition by 10% at the most.
 49. The matrix material according to claim 45, wherein the matrix material is a sponge.
 50. The matrix material according to claim 49, wherein the sponge is a gelatin sponge.
 51. The matrix material according to claim 45, wherein the matrix material is sterile and contained in a sterile, pre-packaged, ready-to-use container.
 52. The matrix material according to claim 45, wherein the hemostatic composition comprises thrombin.
 53. The matrix material according to claim 45, wherein the hemostatic composition comprises one or more bioactive agent(s) that stimulates wound healing.
 54. The matrix material according to claim 45, wherein the hemostatic composition comprises one or more bioactive agent(s) that stimulates wound healing by inhibition of one or more infections of the wound.
 55. The matrix material according to claim 45, wherein the hemostatic composition comprises one or more bioactive agent(s) which comprises one or more anti-fibrinolytic agents.
 56. The matrix material according to claim 45, wherein the hemostatic composition comprises one or more adhesive agents.
 57. The matrix material according to claim 45, where in the hemostatic composition comprises one or more coagulation factors.
 58. The matrix material according to claim 45, wherein the hemostatic composition comprises a fluid component.
 59. The matrix material according to claim 58, wherein the fluid component is an aqueous medium.
 60. The matrix material according to claim 45, wherein the hemostatic composition has a viscosity in the range of 0.1-20 cps.
 61. The matrix material according to claim 45, wherein the hemostatic composition has a surface tension in the range of 0.020 N/m to 0.050 N/m.
 62. The matrix material according to claim 45, wherein the hemostatic composition comprises a single hemostatic agent, said hemostatic agent being thrombin.
 63. The matrix material according to claim 45, wherein the hemostatic composition comprises two or more hemostatic agents.
 64. The matrix material according to claim 45, wherein said matrix material is dry.
 65. A method for making a hemostatic matrix material according to claim 45 comprising the steps of: a) providing a hemostatic matrix material comprising a surface and a plurality of open and interconnected cells, said matrix material comprising gelatin or collagen; and b) applying a hemostatic composition onto the surface of said matrix material.
 66. The method according to claim 65, wherein said method essentially does not alter the physical characteristics of the surface of said matrix material.
 67. The method according to claim 65, wherein said method essentially does not cause any swelling of the matrix material.
 68. The method according to claim 65, wherein said method essentially does not cause any swelling of the surface of said matrix material.
 69. The method according to claim 65, wherein said method essentially does not alter the initial absorption rate of the matrix material.
 70. A method for promoting wound healing in an individual in need thereof, comprising a step of applying to a wound, a hemostatic matrix material comprising a surface and a plurality of open and interconnected cells, said matrix material comprising gelatin or collagen, wherein the surface of said matrix material comprises a hemostatic composition distributed in a uniform manner.
 71. A method for promoting hemostasis in an individual in need thereof, comprising a step of applying to a wound, a hemostatic matrix material comprising a surface and a plurality of open and interconnected cells, said matrix material comprising gelatin or collagen, wherein the surface of said matrix material comprises a hemostatic composition distributed in a uniform manner. 